Substituted 2,3-dihydro-1H-inden-1-one retinoic acid-related orphan nuclear receptor antagonists for treating multiple sclerosis

ABSTRACT

The present invention is directed to compounds, their synthesis, and their use as antagonists, inverse agonists, modulators and or inhibitors of the Retinoic acid-related orphan nuclear receptor γt (RORγt)/RORγ. The compounds of the present invention are useful for modulating RORγt)/RORγ activity and for treating diseases or conditions mediated by RORγt)/RORγ such as for example, disease states associated with immunopathology of human autoimmune diseases such as Multiple Sclerosis (MS), Rheumatoid Arthritis (RA), Inflammatory Colitis, Psoriasis, COPD, Pain, Obesity, Diabetes, Dyslipidemia, Osteoporosis, Asthma, Neurodegenerative diseases and Cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Patent Application61/876,099 filed Sep. 10, 2013, the entirety of which is incorporatedherein by reference.

FIELD OF INVENTION

The present invention is directed to compounds, their synthesis, andtheir use as antagonists, inverse agonists, modulators and or inhibitorsof the Retinoic acid-related Orphan nuclear Receptor γt (RORγt)/RORγ. Inparticular, the present invention is directed to substituted2,3-dihydro-1H-inden-1-one compounds that modulate (RORγt)/RORγ. Thecompounds of the present invention are useful for modulating(RORγt)/RORγ activity and for treating diseases or conditions mediatedby (RORγt)/RORγ such as, for example, disease states associated withimmunopathology of human autoimmune diseases such as Multiple Sclerosis(MS), Rheumatoid Arthritis (RA), Inflammatory Colitis, Psoriasis,Chronic Obstructive Pulmonary Disease (COPD), Pain, Obesity, Diabetes,Dyslipidemia, Osteoporosis, Asthma, Neurodegenerative diseases andCancer.

BACKGROUND OF THE INVENTION

Multiple Sclerosis (MS) is an autoimmune inflammatory demyelinatingdisease of the CNS (central nervous system) that damages the fattymyelin sheaths around the axons of the brain and spinal cord. Thisdamage, destruction, and loss or scarring of the myelin sheaths(sclerosis or plaques) results in a broad spectrum of symptoms. MS is achronic, disabling disease that affects about 400,000 people in theUnited States and nearly 2.5 million people worldwide. MS substantiallyand adversely affects the quality of life of each individual, withsymptoms that include loss of muscle control and strength, fatigue,weakness, loss of vision, spasticity, balance, sensation, bladder andbowel problems, numbness, vision loss, tremors, and adverse mentalfunction such as depression. In the United States alone MS care isestimated to cost nearly $13 billion per year.

Inflammatory cytokines and its receptors have an important role in theprogression of MS lesions, and pro- and anti-inflammatory cytokinelevels have been found to correlate with changes in MS disease activity.Currently, available treatments usually focus on strategies to treatrelapses (oral prednisone and i.v. methylprednisolone), manage symptomsand reduce the progress of the disease with Disease Modifying Drugs(DMDs). It includes relapsing-remitting MS (RRMS) drugs such asImmunomodulatory (β-interferons) therapeutics (Avonex, Betaseron, Rebifand Extavia), Monoclonal Antibodies (Tysabri, Lemtrada), otherimmunosuppressants (Mitoxantrone), Copaxone (glatiramer acetateinjection) and oral agents; Teriflunomide, Fingolimod but none of thesemedications is a cure or prevent recurring symptoms. In addition toexisting oral DMDs such as Fingolimod, and recently approved Tecfidera(BG-12 or Dimethyl Fumarate) and other experimental agents yet to beapproved are in Phase III of clinical development such as Laquinimod,and Masitinib (oral immunomodulators) have been reported to causeopportunistic infections, antibody stimulation, liver and kidneytoxicities. Target specific inhibitors or antagonists should promotemyelination, neuronal repair, neuroprotection Inhibiting the disease andhalting neurodegeneration should eliminate many of these adverse events.

Presently, oral DMT drugs such as Fingolimod, Cladribine, andTecfidera—as well as about 46 other experimental agents in variousstages of clinical development such as Laquinimode, and Masitinib—havebeen reported to cause serious adverse events including opportunisticinfections, antibody stimulation, and liver and kidney toxicities. Thus,there is a continuing need for effective MS drugs with better toxicityprofiles. Target specific inhibitors or antagonists should promotemyelination, neuronal repair, halting neurodegeneration, and shouldeliminate many of these adverse events.

The evidence supporting the risk-benefit profiles for available agentsincluding emerging mAb (Alemtuzumab, Ocrelizumab and Daclizumab) DMTs isyet to fully emerge. Many of these approved and experimental agents yetto be approved create serious adverse events including opportunisticinfections, antibody stimulation, and liver and kidney toxicities.Therefore, MS is still a significant target for innovative therapiesthat can have immunotherapeutic and/or neuroprotective effects on thedisease. This opportunity has strengthened our research focus onclinically relevant RORγt, as an attractive target for the treatment ofMS. RORγt as a nuclear hormone receptor that is a key regulator of Thelper type 17 (Th17) cell differentiation. Th17 cells are normallyproduced in response to infection, but have been linked to thedevelopment of autoimmune diseases. A few pre-clinical stage lead RORγtand RORγ inverse agonists have been reported. For example, azole-typefungicides, T0901317, SR1001, ursolic acid, VPR-66, digoxin, andhexafluoro-substituted sulphamoyl thiazoles had efficacy in autoimmuneencephalomyelitis (EAE) mice models. At least dozen companies;Lycera/Merck, Karo Bio/Pfizer, Phenex/J&J, Orphagen/JT(OR-1050/T0901317, 5 μM), Tempero/GSK (TMP-778, GSK-805), Exelixis/BMS,Teijin/Amgen, Cognoci (COG112), Innovimmune (INV-17), Visionary, 4SCDiscovery and Genentech, have small molecule RORγt programs inpreclinical stage of development. Identification of brain penetrant,RORγt specific antagonists that rescue myelin destruction, restore theaxons of the brain and spinal cord following oral administration will bea significant approach for developing MS therapeutics. The substituted2,3-dihydro-1H-inden-1-one class of compounds claimed in Formula Idiscovered as potent, brain penetrant, orally available RORγtantagonist, and a small molecule candidate compounds as new drugentities for the treatment of such diseases claimed.

The present invention includes small molecule antagonists targetingRetinoic acid-related orphan nuclear receptor γt (RORγt)/RORγ. RORγt isthe key transcription factor and is the master regulator of human Th17(T helper 17) cells, a unique subset of CD4⁺T cells. RORγt controlscellular differentiation, function and InterleukinIL-17 (IL-17 producingT-helper lymphocytes) release by Th17 cells and helps mediate theimmunopathology of human autoimmune diseases such as Multiple Sclerosis(MS), Rheumatoid Arthritis (RA), Inflammatory Colitis, Psoriasis, COPD,Pain, Obesity, Diabetes, Dyslipidemia, Osteoporosis, Asthma,Neurodegenerative diseases and Cancer.

In addition, the substituted 2,3-dihydro-1H-inden-1-one Retinoicacid-related orphan nuclear receptor γt (RORγt)/RORγ antagonists of thepresent invention may be useful in the treatment of multiple cancers,includes gastric, colon cancers, chronic myelogenic leukemia (CML),acute myelogenic leukemia (AML), squamous cell, and bladder carcinomas,medulloblastoma, hepatocellular carcinoma, multiple myeloma, bladder,glioblastoma multiform (GBM), breast and ovarian cancers, Ewing'ssarcoma and bone associated cancer diseases. The methods of treatment ofthe claims of Formula I and its associated claims in the applicationcomprise of administering a safe and effective dose of a compoundsaccording to Formula I or a pharmaceutically-acceptable salt,formulations thereof to a human patients.

Induction of autoimmune MS conditions in mice using MyelinOligodendrocyte Glycoprotein (MOG) or Proteolipid Protein (PLP)immunization causes RORγt activation and differentiation of Th17 cellsthat recruit proinflammatory cytokines IL-17A (IL-17), IL-17F, IL-21 andIL-22 leads to sclerotic myelin and damaged oligodendrocytes. Mice withRORγt deficient T cells have attenuated disease and lacktissue-infiltrating Th17 cells. Hence, RORγt is a key regulator ofimmune homeostasis and is a potential therapeutic target for MultipleSclerosis. Using proprietary internal company proprietary Fragment-FieldDrug Design (FFDD) based technology and uniquely designed specific RORγtisoform assays a novel, potent small molecule substituted2,3-dihydro-1H-inden-1-one series and are specific RORγt antagonist(inverse agonist) and demonstrated its RORγt activity in anRORγt-activated IL-17A Prom/LUCPorter assay in HEK 293 cells, in IL-17release from CD4⁺T cells assays, as well as inhibition of IL-17production in vivo in BALB/c mouse experiments and the effect ofsubstituted 2,3-dihydro-1H-inden-1-one series of Formula I compounds onMOG₃₅₋₅₅ induced in C57/BL6 or BALB/c mice, PLP₁₃₉₋₄₅₁ (ProteolipidProtein) induced in SJL/J mice and Theiler's Murine EncephalitisVirus-Induced Demyelinating Disease (TMEV-IDD) in female BALB/c miceinduced Acute/Relapsing EAE model in female SJL/J mice is claimed inthis application.

SUMMARY OF THE INVENTION

The present invention concerns compounds active on Nuclear hormonereceptor superfamily, specifically RORγt and in general, including RORα,-β, and -γ (NR1F1-3 or RORA-C), its two isoforms, γ1 and γ2(RORγt/ROR-γT) and any mutations of this Nuclear hormone receptorsuperfamily and the use thereof in treating disease and conditionsassociated with regulation of the activity of these Nuclear hormonereceptor superfamily. More specifically the invention concerns compoundsof Formula I as described below. Thus the invention provides novel useof compounds for therapeutic methods involving inhibition and ormodulation of RORα, -β, and -γ specifically RORγt as novel compoundsthat can be used for the therapeutic methods involving modulation of theimmunopathology of human autoimmune diseases such as Multiple Sclerosis(MS), Rheumatoid Arthritis (RA), Inflammatory Colitis, Psoriasis, COPD,Pain, Obesity, Diabetes, Dyslipidemia, Osteoporosis, Asthma,Neurodegenerative diseases and Cancer.

The present invention relates to compounds according to Formulas I: topharmaceutically acceptable composition, salts thereof, their synthesisand their use as RORgt and RORg inhibitors including such compounds andmethods of their use in the treatment of various immunopathology ofhuman autoimmune diseases such as Multiple Sclerosis (MS), RheumatoidArthritis (RA), Inflammatory Colitis, Psoriasis, COPD, Pain, Obesity,Diabetes, Dyslipidemia, Osteoporosis, Asthma, Neurodegenerative diseasesand Cancer.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: X-ray crystal structure RORγ in complex with substituted2,3-dihydro-1H-inden-1-one containing RORγt antagonist.

FIG. 2A: Effect of substituted 2,3-dihydro-1H-inden-1-one seriescontaining RORg antagonists on RORγt-mediated IL-17A promoter activity.

FIG. 2B: RORγt-mediated IL-17A Dose-response curve.

FIG. 3A: Effect of substituted 2,3-dihydro-1H-inden-1-one series RORgantagonists on RORγt-mediated IL-17A promoter activity.

FIG. 3B: RORγt-mediated IL-17A Dose-response curve.

FIG. 4: Cytokine IL-17 inhibition by substituted2,3-dihydro-1H-inden-1-one series.

FIG. 5: Effect of Test Compound on MOG35-55 Induced EAE in FemaleC57/BL6 Mice.

FIG. 6: Effect of Test Compound & Fingolimod Administration on BodyWeight of EAE Mice (Female C57/BL6).

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the present invention are described by Formula I:

or pharmaceutically acceptable salts thereof, wherein:

X is O or S;

R¹ is or

R¹ is C₁₋₄alkyl optionally substituted with 1-6 independent halosubstituents; or

R¹ is phenyl, pyridinyl, or pyrazolyl, each optionally substituted with1-5 independent halo, trifluoromethyl, (trifluoromethyl)thio,trifluoromethoxy, 1,1,1,3,3,3,-hexafluoro-2-hydroxypropan-2-yl,

substituents;

m is 0 or 1;

the dotted line indicates an optional double bond when m=1;

R² or R³ each independently is halo, —OH, —CN, —OCH₃, —O—S(O)₂CH₂CH₃,

or R² or R³ each independently is phenyl optionally substituted with 0-5independent halo, trifluoromethoxy substituents;

n is 2 or 3 carbon chain; and

R⁴ is H, OH, OCH₃, or —O—S(O)₂CH₂CH₃.

Compounds of the present invention can be made using the compounds

as an intermediate. Accordingly, the present invention includes thesecompounds.

In an aspect of the invention, compounds of the present invention aredescribed by Formula (I) and pharmaceutically acceptable salts thereof,wherein X is O, and the other variables are as defined above for Formula(I).

In an embodiment of the aspect of the invention, compounds of thepresent invention are described by Formula (I) and pharmaceuticallyacceptable salts thereof, wherein X is O, R¹ is

and the other variables are as defined above for Formula (I).

In another embodiment of the aspect of the invention, compounds of thepresent invention are described by Formula (I) and pharmaceuticallyacceptable salts thereof, wherein X is O, R¹ is

and the other variables are as defined above for Formula (I).

In yet another embodiment of the aspect of the invention, compounds ofthe present invention are described by Formula (I) and pharmaceuticallyacceptable salts thereof, wherein X is O, R¹ is C₁₋₄alkyl optionallysubstituted with 1-6 independent halo substituents and the othervariables are as defined above for Formula (I).

In still another embodiment of the aspect of the invention, compounds ofthe present invention are described by Formula (I) and pharmaceuticallyacceptable salts thereof, wherein X is O, R1 is phenyl, optionallysubstituted with 1-5 independent halo, trifluoromethyl,(trifluoromethyl)thio,

substituents, and the other variables are as defined above for Formula(I).

In another embodiment of the aspect of the invention, compounds of thepresent invention are described by Formula (I) and pharmaceuticallyacceptable salts thereof, wherein X is O, R1 is pyridinyl, optionallysubstituted with 1-5 independent halo, trifluoromethyl,(trifluoromethyl)thio,

substituents, and the other variables are as defined above for Formula(I).

In still another embodiment of the aspect of the invention, compounds ofthe present invention are described by Formula (I) and pharmaceuticallyacceptable salts thereof, wherein X is O, R1 is pyrazolyl optionallysubstituted with 1-5 independent halo, trifluoromethyl,(trifluoromethyl)thio,

substituents, and the other variables are as defined above for Formula(I).

In an aspect of the present invention, compounds of the presentinvention are described by Formula (Ia) and pharmaceutically acceptablesalts thereof,

wherein

X is O or S;

R¹ is

or

R¹ is C₁₋₄alkyl optionally substituted with 1-6 independent halosubstituents; or

R¹ is phenyl, pyridinyl, or pyrazolyl, each optionally substituted with1-5 independent halo, trifluoromethyl, (trifluoromethyl)thio,

substituents;

the dotted line indicates an optional double bond;

X¹ and X² are independently C, N, or O; wherein at least one is not C;

R⁵ is absent, halo, or C₀₋₄alkyl.

and R⁶ is halo, or C₀₋₄alkyl.

In an aspect of the present invention, compounds of the presentinvention are described by Formula (Ia) and pharmaceutically acceptablesalts thereof,

wherein

X is O or S;

R¹ is

or

R¹ is C₁₋₄alkyl optionally substituted with 1-6 independent halosubstituents; or

R¹ is phenyl, pyridinyl, or pyrazolyl, each optionally substituted with1-5 independent halo, trifluoromethyl, (trifluoromethyl)thio,

substituents;

the dotted line indicates an optional double bond

X¹ and X² are independently C, N, or O; wherein at least one is not C;

R⁵ is absent, halo, or C₀₋₄alkyl.

and R⁶ is halo, or C₀₋₄alkyl.

In an aspect of the present invention, compounds of the presentinvention are described by Formula (Ia) and pharmaceutically acceptablesalts thereof,

wherein

X is O or S;

R¹ is

or

R¹ is C₁₋₄alkyl optionally substituted with 1-6 independent halosubstituents; or

R¹ is phenyl, pyridinyl, or pyrazolyl, each optionally substituted with1-5 independent halo, trifluoromethyl, (trifluoromethyl)thio,

substituents;

the dotted line indicates an optional double bond.

The compounds of the present invention include:

Compounds of the invention further include:

Unless otherwise stated the following terms used in the specificationand claims have the meanings discussed below:

“Alkyl” refers to a saturated straight or branched hydrocarbon radicalof one to six carbon atoms, preferably one to four carbon atoms, e.g.,methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl,hexyl, and the like, preferably methyl, ethyl, propyl, or 2-propyl.Representative saturated straight chain alkyls include methyl, ethyl,n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; while saturatedbranched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl,isopentyl, and the like. Cyclic alkyls are referred to herein as a“cycloalkyl.”

Unsaturated alkyls contain at least one double or triple bond betweenadjacent carbon atoms (referred to as an “alkenyl” or “alkynyl”,respectively.) Representative straight chain and branched alkenylsinclude ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl,1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl,2,3-dimethyl-2-butenyl, and the like; while representative straightchain and branched alkynyls include acetylenyl, propynyl, 1-butynyl,2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, and the like.

“C₀₋₄alkyl” refers to an alkyl with 0, 1, 2, 3, or 4 carbon atoms.C₀₋₄alkyl with 0 carbon atoms is a hydrogen atom when terminal and is adirect bond when linking.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene, ethylene,2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene,and the like, preferably methylene, ethylene, or propylene.

“Cycloalkyl” refers to a saturated cyclic hydrocarbon radical of threeto eight carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl.

“Alkoxy” means a radical —OR_(a) where R_(a) is an alkyl as definedabove, e.g., methoxy, ethoxy, propoxy, butoxy and the like.

“Halo” means fluoro, chloro, bromo, or iodo, preferably fluoro andchloro.

“Haloalkyl” means alkyl substituted with one or more, preferably one,two or three, same or different halo atoms, e.g., —CH₂Cl, —CF₃, —CH₂CF₃,—CH₂CCl₃, and the like.

“Haloalkoxy” means a radical —OR_(b) where R_(b) is an haloalkyl asdefined above, e.g., trifluoromethoxy, trichloroethoxy,2,2-dichloropropoxy, and the like.

“Acyl” means a radical —C(O)R_(c) where R_(c) is hydrogen, alkyl, orhaloalkyl as defined herein, e.g., formyl, acetyl, trifluoroacetyl,butanoyl, and the like.

“Aryl” refers to an all-carbon monocyclic or fused-ring polycyclic(i.e., rings which share adjacent pairs of carbon atoms) groups of 6 to12 carbon atoms having a completely conjugated pi-electron system.Examples, without limitation, of aryl groups are phenyl, naphthyl andanthracenyl. The aryl group may be substituted or unsubstituted. Unlessspecifically stated otherwise, “substituted aryl” refers to the arylgroup being substituted with one or more, more preferably one, two orthree, even more preferably one or two substituents independentlyselected from the group consisting of alkyl (wherein the alkyl may beoptionally substituted with one or two substituents), haloalkyl, halo,hydroxy, alkoxy, mercapto, alkylthio, cyano, acyl, nitro, phenoxy,heteroaryl, heteroaryloxy, haloalkyl, haloalkoxy, carboxy,alkoxycarbonyl, amino, alkylamino dialkylamino, aryl, heteroaryl,carbocycle or heterocycle (wherein the aryl, heteroaryl, carbocycle orheterocycle may be optionally substituted).

“Heteroaryl” refers to a monocyclic or fused ring (i.e., rings whichshare an adjacent pair of atoms) group of 5 to 12 ring atoms containingone, two, three or four ring heteroatoms selected from N, O, or S, theremaining ring atoms being C, and, in addition, having a completelyconjugated pi-electron system. Examples, without limitation, ofunsubstituted heteroaryl groups are pyrrole, furan, thiophene,imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline,isoquinoline, purine, triazole, tetrazole, triazine, and carbazole. Theheteroaryl group may be unsubstituted or substituted, such as, forexample, 5-methylthiazolyl. Unless specifically stated otherwise,“substituted heteroaryl” refers to the heteroaryl group beingsubstituted with one or more, more preferably one, two or three, evenmore preferably one or two substituents independently selected from thegroup consisting of alkyl (wherein the alkyl may be optionallysubstituted with one or two substituents), haloalkyl, halo, hydroxy,alkoxy, mercapto, alkylthio, cyano, acyl, nitro, haloalkyl, haloalkoxy,carboxy, alkoxycarbonyl, amino, alkylamino dialkylamino, aryl,heteroaryl, carbocycle or heterocycle (wherein the aryl, heteroaryl,carbocycle or heterocycle may be optionally substituted).

“Carbocycle” refers to a saturated, unsaturated or aromatic ring systemhaving 3 to 14 ring carbon atoms. The term “carbocycle”, whethersaturated or partially unsaturated, also refers to rings that areoptionally substituted. The term “carbocycle” includes aryl. The term“carbocycle” also includes aliphatic rings that are fused to one or morearomatic or nonaromatic rings, such as in a decahydronaphthyl ortetrahydronaphthyl, where the radical or point of attachment is on thealiphatic ring. The carbocycle group may be substituted orunsubstituted. Unless specifically stated otherwise, “substitutedcarbocyle” refers to the carbocycle group being substituted with one ormore, more preferably one, two or three, even more preferably one or twosubstituents independently selected from the group consisting of alkyl(wherein the alkyl may be optionally substituted with one or twosubstituents), haloalkyl, halo, hydroxy, alkoxy, mercapto, alkylthio,cyano, acyl, nitro, haloalkyl, haloalkoxy, carboxy, alkoxycarbonyl,amino, alkylamino dialkylamino, aryl, heteroaryl, carbocycle orheterocycle (wherein the aryl, heteroaryl, carbocycle or heterocycle maybe optionally substituted).

“Heterocycle” refers to a saturated, unsaturated or aromatic cyclic ringsystem having 3 to 14 ring atoms in which one, two or three ring atomsare heteroatoms selected from N, O, or S(O)_(m) (where m is an integerfrom 0 to 2), the remaining ring atoms being C, where one or two C atomsmay optionally be replaced by a carbonyl group. The term “heterocycle”includes heteroaryl. Unless specifically stated otherwise, “substitutedheterocyclyl” refers to the heterocyclyl ring being substitutedindependently with one or more, preferably one, two, or threesubstituents selected from alkyl (wherein the alkyl may be optionallysubstituted with one or two substituents), haloalkyl, cycloalkylamino,cycloalkyl or cycloalkyl-alkyl, cycloalkyl-aminoalkyl, cycloalkyl-alkylamino-alkyl, cyanoalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino,alkylamino, dialkylamino, hydroxyalkyl, carboxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, aralkyl, heteroaralkyl, aryl,heteroaryl, carbocycle, heterocycle (wherein the aryl, heteroaryl,carbocycle or heterocycle may be optionally substituted), aralkyl,heteroaralkyl, saturated or unsaturated heterocycloamino, saturated orunsaturated heterocycloaminoalkyl, and —COR_(d) (where R_(d) is alkyl).More specifically the term heterocyclyl includes, but is not limited to,tetrahydropyranyl, 2,2-dimethyl-1,3-dioxolane, piperidino,N-methylpiperidin-3-yl, piperazino, N-methylpyrrolidin-3-yl,pyrrolidino, morpholino, 4-cyclopropylmethylpiperazino, thiomorpholino,thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide,4-ethyloxycarbonylpiperazino, 3-oxopiperazino, 2-imidazolidone,2-pyrrolidinone, 2-oxohomopiperazino, tetrahydropyrimidin-2-one, and thederivatives thereof, including2-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridinyl. In certainembodiments, the heterocycle group is optionally substituted with one ortwo substituents independently selected from halo, alkyl, alkylsubstituted with carboxy, ester, hydroxy, alkylamino, saturated orunsaturated heterocycloamino, saturated or unsaturatedheterocycloaminoalkyl, or dialkylamino

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “heterocyclic group optionallysubstituted with an alkyl group” means that the alkyl may but need notbe present, and the description includes situations where theheterocycle group is substituted with an alkyl group and situationswhere the heterocycle group is not substituted with the alkyl group.

Lastly, unless specifically stated otherwise, the term “substituted” asused herein means any of the above groups (e.g., alkyl, aryl,heteroaryl, carbocycle, heterocycle, etc.) wherein at least one hydrogenatom is replaced with a substituent. In the case of an oxo substituent(“═O”) two hydrogen atoms are replaced. “Substituents” within thecontext of this invention, if not specified, include halogen, hydroxy,oxo, cyano, nitro, amino, alkylamino, dialkylamino, alkyl, alkoxy,thioalkyl, haloalkyl (e.g., —CF₃), hydroxyalkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, heterocycle, substitutedheterocycle, heterocyclealkyl, substituted heterocyclealkyl,—NR_(e)R_(f), —NR_(e)C(═O)R_(f), —NR_(e)C(═O)NR_(e)R_(f),—NR_(e)C(═O)OR_(f), —NR_(e)SO₂R_(f), —OR_(e), —C(═O)R_(e)—C(═O)OR_(e),—C(═O)NR_(e)R_(f), —OC(═O)NR_(e)R_(f), —SH, —SR_(e), —SOR_(e),—S(═O)₂R_(e), —OS(═O)₂R_(e), —S(═O)₂OR_(e), wherein R_(e) and R_(f) arethe same or different and independently hydrogen, alkyl, haloalkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, heterocycle, substituted heterocycle,heterocyclealkyl or substituted heterocyclealkyl.

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers”. Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers”. Stereoisomers that arenot mirror images of one another are termed “diastereomers” and thosethat are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, itis bonded to four different groups; a pair of enantiomers is possible.An enantiomer can be characterized by the absolute configuration of itsasymmetric center and is described by the R- and S-sequencing rules ofCahn and Prelog (Cahn, R., Ingold, C., and Prelog, V. Angew. Chem.78:413-47, 1966; Angew. Chem. Internat. Ed. Eng. 5:385-415, 511, 1966),or by the manner in which the molecule rotates the plane of polarizedlight and designated as dextrorotatory or levorotatory (i.e., as (+) or(−)-isomers respectively). A chiral compound can exist as eitherindividual enantiomer or as a mixture thereof. A mixture containingequal proportions of the enantiomers is called a “racemic mixture”.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers andmixtures, racemic or otherwise, thereof. The methods for thedetermination of stereochemistry and the separation of stereoisomers arewell-known in the art (see discussion in Ch. 4 of ADVANCED ORGANICCHEMISTRY, 4^(th) edition, March, J., John Wiley and Sons, New YorkCity, 1992).

The compounds of the present invention may exhibit the phenomena oftautomerism and structural isomerism. This invention encompasses anytautomeric or structural isomeric form and mixtures thereof whichpossess the ability to modulate (RORγt)/RORγ activity and is not limitedto, any one tautomeric or structural isomeric form.

It is contemplated that a compound of the present invention would bemetabolized by enzymes in the body of the organism such as human beingto generate a metabolite that can modulate the activity of the proteinkinases. Such metabolites are within the scope of the present invention.

A compound of the present invention or a pharmaceutically acceptablesalt thereof can be administered as such to a human patient or can beadministered in pharmaceutical compositions in which the foregoingmaterials are mixed with suitable carriers or excipient(s). Techniquesfor formulation and administration of drugs may be found, for example,in REMINGTON'S PHARMACOLOGICAL SCIENCES, Mack Publishing Co., Easton,Pa., latest edition.

A “pharmaceutical composition” refers to a mixture of one or more of thecompounds described herein or pharmaceutically acceptable salts orprodrugs thereof, with other chemical components, such aspharmaceutically acceptable excipients. The purpose of a pharmaceuticalcomposition is to facilitate administration of a compound to anorganism.

“Pharmaceutically acceptable excipient” refers to an inert substanceadded to a pharmaceutical composition to further facilitateadministration of a compound. Examples, without limitation, ofexcipients include calcium carbonate, calcium phosphate, various sugarsand types of starch, cellulose derivatives, gelatin, vegetable oils andpolyethylene glycols.

“Pharmaceutically acceptable salt” refers to those salts which retainthe biological effectiveness and properties of the parent compound. Suchsalts may include: (1) acid addition salt which is obtained by reactionof the free base of the parent compound with inorganic acids such ashydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid,sulfuric acid, and perchloric acid and the like, or with organic acidssuch as acetic acid, oxalic acid, (D)- or (L)-malic acid, maleic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, tartaric acid, citric acid, succinic acid or malonicacid and the like, preferably hydrochloric acid or (L)-malic acid; or(2) salts formed when an acidic proton present in the parent compoundeither is replaced by a metal ion, e.g., an alkali metal ion, analkaline earth ion, or an aluminum ion; or coordinates with an organicbase such as ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like.

The compound of the present invention may also act, or be designed toact, as a prodrug. A “prodrug” refers to an agent, which is convertedinto the parent drug in vivo. Prodrugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent drug is not. The prodrug may also have improved solubility inpharmaceutical compositions over the parent drug. An example, withoutlimitation, of a prodrug would be a compound of the present invention,which is, administered as an ester (the “prodrug”), phosphate, amide,carbamate, or urea.

“Therapeutically effective amount” refers to that amount of the compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disorder being treated. In reference to the treatment ofMS, a therapeutically effective amount refers to that amount which hasthe effect of: (1) ameliorating loss of muscle control and strength, (2)lessoning fatigue or weakness, (3) stabilizing loss of vision, (4)decreasing spasticity, (5) increased balance, (6) lessoning bladder andbowel problems, (7) decreasing numbness, or relieving one or moresymptoms associated with MS.

The term “disease”, as used herein, means any disease or otherdeleterious condition in which Retinoic acid-related orphan nuclearreceptor γt (RORγt)/RORγ is known to play a role. The term “disease”also means those diseases or conditions that are alleviated by treatmentwith (RORγt)/RORγ modulators.

The term “(RORγt)/RORγ activity-mediated condition” or “disease”, asused herein, means any disease or other deleterious condition in which(RORγt)/RORγ activity is known to play a role. The term “(RORγt)/RORγactivity-mediated condition” also means those diseases or conditionsthat are alleviated by treatment with a (RORγt)/RORγ inhibitor.

As used herein, “administer” or “administration” refers to the deliveryof an inventive compound or of a pharmaceutically acceptable saltthereof or of a pharmaceutical composition containing an inventivecompound or a pharmaceutically acceptable salt thereof of this inventionto an organism for the purpose of prevention or treatment of a(RORγt)/RORγ related disorder.

Suitable routes of administration may include, without limitation, oral,rectal, transmucosal or intestinal administration or intramuscular,subcutaneous, intramedullary, intrathecal, direct intraventricular,intravenous, intravitreal, intraperitoneal, intranasal, or intraocularinjections. In certain embodiments, the preferred routes ofadministration are oral and intravenous.

Pharmaceutical compositions of the present invention may be manufacturedby processes well known in the art, e.g., by means of conventionalmixing, dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes.

Pharmaceutical compositions for use in accordance with the presentinvention may be formulated in any conventional manner using one or morephysiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen.

For injection, the compounds of the invention may be formulated inaqueous solutions, preferably in physiologically compatible buffers suchas Hanks' solution, Ringer's solution, or physiological saline buffer.For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants aregenerally known in the art.

For oral administration, the compounds can be formulated by combiningthe active compounds with pharmaceutically acceptable carriers wellknown in the art. Such carriers enable the compounds of the invention tobe formulated as tablets, pills, lozenges, dragees, capsules, liquids,gels, syrups, slurries, suspensions and the like, for oral ingestion bya patient. Pharmaceutical preparations for oral use can be made using asolid excipient, optionally grinding the resulting mixture, andprocessing the mixture of granules, after adding other suitableauxiliaries if desired, to obtain tablets or dragee cores. Usefulexcipients are, in particular, fillers such as sugars, includinglactose, sucrose, mannitol, or sorbitol, cellulose preparations such as,for example, maize starch, wheat starch, rice starch and potato starchand other materials such as gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinyl-pyrrolidone (PVP). If desired, disintegrating agents may beadded, such as cross-linked polyvinyl pyrrolidone, agar, or alginicacid. A salt such as sodium alginate may also be used.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical compositions which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, a binder such as starch, and/or a lubricant such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. Stabilizers may be added in these formulations, also.Pharmaceutical compositions which may also be used include hard gelatincapsules. The capsules or pills may be packaged into brown glass orplastic bottles to protect the active compound from light. Thecontainers containing the active compound capsule formulation arepreferably stored at controlled room temperature (15-30° C.).

For administration by inhalation, the compounds for use according to thepresent invention may be conveniently delivered in the form of anaerosol spray using a pressurized pack or a nebulizer and a suitablepropellant, e.g., without limitation, dichlorodifluoromethane,trichlorofluoromethane, dichlorotetra-fluoroethane or carbon dioxide. Inthe case of a pressurized aerosol, the dosage unit may be controlled byproviding a valve to deliver a metered amount. Capsules and cartridgesof, for example, gelatin for use in an inhaler or insufflator may beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch.

The compounds may also be formulated for parenteral administration,e.g., by bolus injection or continuous infusion. Formulations forinjection may be presented in unit dosage form, e.g., in ampoules or inmulti-dose containers, with an added preservative. The compositions maytake such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulating materials such assuspending, stabilizing and/or dispersing agents.

Pharmaceutical compositions for parenteral administration includeaqueous solutions of a water soluble form, such as, without limitation,a salt, of the active compound. Additionally, suspensions of the activecompounds may be prepared in a lipophilic vehicle. Suitable lipophilicvehicles include fatty oils such as sesame oil, synthetic fatty acidesters such as ethyl oleate and triglycerides, or materials such asliposomes. Aqueous injection suspensions may contain substances whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may alsocontain suitable stabilizers and/or agents that increase the solubilityof the compounds to allow for the preparation of highly concentratedsolutions.

Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile, pyrogen-free water,before use.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, using, e.g., conventional suppositorybases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds mayalso be formulated as depot preparations. Such long acting formulationsmay be administered by implantation (for example, subcutaneously orintramuscularly) or by intramuscular injection. A compound of thisinvention may be formulated for this route of administration withsuitable polymeric or hydrophobic materials (for instance, in anemulsion with a pharmacologically acceptable oil), with ion exchangeresins, or as a sparingly soluble derivative such as, withoutlimitation, a sparingly soluble salt.

A non-limiting example of a pharmaceutical carrier for the hydrophobiccompounds of the invention is a cosolvent system comprising benzylalcohol, a nonpolar surfactant, a water-miscible organic polymer and anaqueous phase such as the VPD cosolvent system. VPD is a solution of 3%w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80,and 65% w/v polyethylene glycol 300, made up to volume in absoluteethanol. The VPD cosolvent system (VPD: D5W) consists of VPD diluted 1:1with a 5% dextrose in water solution. This cosolvent system dissolveshydrophobic compounds well, and itself produces low toxicity uponsystemic administration. Naturally, the proportions of such a cosolventsystem may be varied considerably without destroying its solubility andtoxicity characteristics. Furthermore, the identity of the cosolventcomponents may be varied: for example, other low-toxicity nonpolarsurfactants may be used instead of polysorbate 80, the fraction size ofpolyethylene glycol may be varied, other biocompatible polymers mayreplace polyethylene glycol, e.g., polyvinyl pyrrolidone, and othersugars or polysaccharides may substitute for dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are well knownexamples of delivery vehicles or carriers for hydrophobic drugs. Inaddition, certain organic solvents such as dimethylsulfoxide also may beemployed, although often at the cost of greater toxicity.

Additionally, the compounds may be delivered using a sustained-releasesystem, such as semipermeable matrices of solid hydrophobic polymerscontaining the therapeutic agent. Various sustained-release materialshave been established and are well known by those skilled in the art.Sustained-release capsules may, depending on their chemical nature,release the compounds for a few weeks up to over 100 days. Depending onthe chemical nature and the biological stability of the therapeuticreagent, additional strategies for protein stabilization may beemployed.

The pharmaceutical compositions herein also may comprise suitable solidor gel phase carriers or excipients. Examples of such carriers orexcipients include, but are not limited to, calcium carbonate, calciumphosphate, various sugars, starches, cellulose derivatives, gelatin, andpolymers such as polyethylene glycols.

Many of the (RORγt)/RORγ modulating compounds of the invention may beprovided as physiologically acceptable salts wherein the claimedcompound may form the negatively or the positively charged species.Examples of salts in which the compound forms the positively chargedmoiety include, without limitation, quaternary ammonium (definedelsewhere herein), salts such as the hydrochloride, sulfate, carbonate,lactate, tartrate, malate, maleate, succinate wherein the nitrogen atomof the quaternary ammonium group is a nitrogen of the selected compoundof this invention which has reacted with the appropriate acid. Salts inwhich a compound of this invention forms the negatively charged speciesinclude, without limitation, the sodium, potassium, calcium andmagnesium salts formed by the reaction of a carboxylic acid group in thecompound with an appropriate base (e.g. sodium hydroxide (NaOH),potassium hydroxide (KOH), calcium hydroxide (Ca(OH)₂), etc).

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are contained in anamount sufficient to achieve the intended purpose, e.g., the modulationof protein kinase activity and/or the treatment or prevention of aprotein kinase-related disorder.

More specifically, a therapeutically effective amount means an amount ofcompound effective to prevent, alleviate or ameliorate symptoms ofdisease or prolong the survival of the subject being treated.

Determination of a therapeutically effective amount is well within thecapability of those skilled in the art, especially in light of thedetailed disclosure provided herein.

For any compound used in the methods of the invention, thetherapeutically effective amount or dose can be estimated initially fromcell culture assays. Then, the dosage can be formulated for use inanimal models so as to achieve a circulating concentration range thatincludes the IC₅₀ as determined in cell culture (i.e., the concentrationof the test compound which achieves a half-maximal inhibition of the(RORγt)/RORγ, or surrogate marker activity). Such information can thenbe used to more accurately determine useful doses in humans.

Toxicity and therapeutic efficacy of the compounds described herein canbe determined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., by determining the IC₅₀ and the LD₅₀ (bothof which are discussed elsewhere herein) for a subject compound. Thedata obtained from these cell culture assays and animal studies can beused in formulating a range of dosage for use in humans. The dosage mayvary depending upon the dosage form employed and the route ofadministration utilized. The exact formulation, route of administrationand dosage can be chosen by the individual physician in view of thepatient's condition. (See, e.g., GOODMAN & GILMAN'S THE PHARMACOLOGICALBASIS OF THERAPEUTICS, Ch. 3, 9^(th) ed., Ed. by Hardman, J., andLimbard, L., McGraw-Hill, New York City, 1996, p. 46.)

Dosage amount and interval may be adjusted individually to provideplasma levels of the active species which are sufficient to maintain thekinase modulating effects. These plasma levels are referred to asminimal effective concentrations (MECs). The MEC will vary for eachcompound but can be estimated from in vitro data, e.g., theconcentration necessary to achieve 50-90% inhibition of (RORγt)/RORγ, orsurrogate marker may be ascertained using the assays described herein.Dosages necessary to achieve the MEC will depend on individualcharacteristics and route of administration. HPLC assays or bioassayscan be used to determine plasma concentrations.

Dosage intervals can also be determined using MEC value. Compoundsshould be administered using a regimen that maintains plasma levelsabove the MEC for 10-90% of the time, preferably between 30-90% and mostpreferably between 50-90%.

At present, the therapeutically effective amounts of compounds of thepresent invention may range from approximately 2.5 mg/m² to 1500 mg/m²per day. Additional illustrative amounts range from 0.2-1000 mg/qid,2-500 mg/qid, and 20-250 mg/qid.

In cases of local administration or selective uptake, the effectivelocal concentration of the drug may not be related to plasmaconcentration, and other procedures known in the art may be employed todetermine the correct dosage amount and interval.

The amount of a composition administered will, of course, be dependenton the subject being treated, the severity of the affliction, the mannerof administration, the judgment of the prescribing physician, etc.

The compositions may, if desired, be presented in a pack or dispenserdevice, such as an FDA approved kit, which may contain one or more unitdosage forms containing the active ingredient. The pack may for examplecomprise metal or plastic foil, such as a blister pack. The pack ordispenser device may be accompanied by instructions for administration.The pack or dispenser may also be accompanied by a notice associatedwith the container in a form prescribed by a governmental agencyregulating the manufacture, use or sale of pharmaceuticals, which noticeis reflective of approval by the agency of the form of the compositionsor of human or veterinary administration. Such notice, for example, maybe of the labeling approved by the U.S. Food and Drug Administration forprescription drugs or of an approved product insert. Compositionscomprising a compound of the invention formulated in a compatiblepharmaceutical carrier may also be prepared, placed in an appropriatecontainer, and labeled for treatment of an indicated condition. Suitableconditions indicated on the label may include treatment of a tumor,inhibition of angiogenesis, treatment of fibrosis, diabetes, and thelike.

As mentioned above, the compounds and compositions of the invention willfind utility in a broad range of diseases and conditions mediated byprotein kinases, including diseases and conditions mediated by(RORγt)/RORγ activity. Such diseases may include by way of example andnot limitation, Multiple Sclerosis (MS), Rheumatoid Arthritis (RA),Inflammatory Colitis, Psoriasis, COPD, Pain, Obesity, Diabetes,Dyslipidemia, Osteoporosis, Asthma, Neurodegenerative diseases andCancer.

The invention will be further understood upon consideration of thefollowing non-limiting Examples. In other aspects or embodiments includeany of the compounds in TABLE 1A and 1B that fall with in the scope ofany of the embodiments described above of the compounds of Formula I orpharmaceuticals acceptable salts thereof.

TABLE 1A Substituted 2,3-dihydro-1H-inden-1-one containing RORγAntagonists Example ID Structure Name MW 16

2-(4-chloro-2-fluorobenzyl)-6- methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one  389.8* 20

2-(4-chloro-2-fluorobenzyl)-5-(3,4- dimethylpiperazin-1-yl)-6-methoxy-2,3-dihydro-1H-inden-1- one 414.9 23

2-((1-benzylpiperidin-4- yl)methyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden- 1-one  435.2* 25

2-((1-benzylpiperidin-4- yl)methyl)-5-(3,4- dimethylpiperazin-1-yl)-6-methoxy-2,3-dihydro-1H-inden-1- one 461.6 28

2-(2,4-difluorobenzyl)-6-methoxy- 5-morpholino-2,3-dihydro-1H-inden-1-one  373.9* 31

6-methoxy-5-morpholino-2-(3- (trifluoromethoxy)benzyl)-2,3-dihydro-1H-inden-1-one  422.1* 34

6-methoxy-2-(3-((1- methylpiperidin-4 yl)amino)-5(trifluoromethoxy)benzyl)-5- morpholino-2,3-dihydro-1H-inden- 1-one533.2 30

(E)-2-(3-bromo-5- (trifluoromethoxy)benzylidene)-6-methoxy-5-morpholino-2,3- dihydro-1H-inden-1-one 498.2 32

2-(3-bromo-5- (trifluoromethoxy)benzyl)-6- methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 500.3 37

6-methoxy-5-morpholino-2-(3- (trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-1-one  406.0* 39

6-methoxy-2-(3-((1- methylpiperidin-4-yl)amino)-5-(trifluoromethyl)benzyl)-5- morpholino-2,3-dihydro-1H-inden- 1-one 517.26 42

2-(2,6-difluorobenzyl)-6-methoxy- 5-morpholino-2,3-dihydro-1H-inden-1-one  374.0* 44

2-(2,6-difluoro-3-((1- methylpiperidin-4- yl)amino)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden- 1-one  485.25 47

2-((4-chloro-2-morpholinothiazol- 5-yl)methyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden- 1-one  463.98 50

2-(3-chloro-5- (trifluoromethyl)benzyl)-6- methoxy-5-morpholino-2,3 -dihydro-1H-inden-1-one  440.0* 53

2-(5-chloro-2-(trifluoromethyl) benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one  440.0* 56

2-(4-chloro-2- (trifluoromethyl)benzyl)-6- methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 439.8 59

2-(2-chloro-6- (trifluoromethyl)benzyl)-6- methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 439.8 62

2-((2-chloro-5- (trifluoromethyl)pyridin-3 - yl)methyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden- 1-one 440.8 65

N-(2-((6-methoxy-5-morpholino-1- oxo-2,3-dihydro-1H-inden-2-yl)methyl)-4- (trifluoromethyl)phenyl)pivalamide 504.5 68

6-methoxy-5-morpholino-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H-inden- 1-one  407.0* 71

6-methoxy-5-morpholino-2-((6- (trifluoromethyl)pyridin-3-yl)methyl)-2,3-dihydro-1H-inden- 1-one  407.0* 74

6-methoxy-5-morpholino-2-(4- ((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-1-one  438.0* 77

2-(2-fluoro-5- (trifluoromethyl)benzyl)-6- methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one  424.0* 80

2-(2-fluoro-3- (trifluoromethyl)benzyl)-6- methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 424.0 83

6-methoxy-5-morpholino-2-((6- (trifluoromethyl)pyridin-3-yl)methyl)-2,3-dihydro-1H-inden- 1-one 406.4 86

6-methoxy-5-morpholino-2-(4- (trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-1-one  406.0* 89

2-(4-chloro-3- (trifluoromethyl)benzyl)-6- methoxy-5-morpholino-2,3 -dihydro-1H-inden-1-one  439.9* 92

2-(3-chloro-4- (trifluoromethyl)benzyl)-6- methoxy-5-morpholino-2,3 -dihydro-1H-inden-1-one  440.0* 95

6-methoxy-2-((3-methyl-1H- pyrazol-5-yl)methyl)-5-morpholino-2,3-dihydro-1H-inden- 1-one  342.0* 98

6-methoxy-5-morpholino-2-(4,4,4- trifluorobutyl)-2,3-dihydro-1H-inden-1-one 357.3 103

6-methoxy-5-(4-methylpiperazin- 1-yl)-2-(3 -(trifluoromethyl)benzyl)-2,3- dihydro-1H-inden-1-one 418.4 106

6-methoxy-5-(4-methylpiperazin- 1-yl)-2-(3 -((trifluoromethyl)thio)benzyl)-2,3- dihydro-1H-inden-1-one  451.0* 110

2-(2-chloro-3- (trifluoromethyl)benzyl)-6-methoxy-5-(4-methylpiperazin-1- yl)-2,3-dihydro-1H-inden-1-one 452.9 113

6-methoxy-5-(4-methylpiperazin- 1-yl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H-inden- 1-one 419.4 117

6-methoxy-5-(piperazin-1-yl)-2-(4- ((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-1-one 436.5 120

5,6-dimethoxy-4-morpholino-2-(4- ((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-1-one 467.5 123

5,6-dimethoxy-4-morpholino-2- ((3-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H-inden- 1-one 436.4 125

5,6-dimethoxy-4-(4- methylpiperazin-1-yl)-2-(4-((trifluoromethyl)thio)benzyl)-2,3 - dihydro-1H-inden-1-one 480.5 128

5,6-dimethoxy-4-(4- methylpiperazin-1-yl)-2-((3-(trifluoromethyl)pyridin-2- yl)methyl)-2,3-dihydro-1H-inden- 1-one 449.4131

5,6-dimethoxy-4-(4- methylpiperidin-1-yl)-2-(4-((trifluoromethyl)thio)benzyl)-2,3- dihydro-1H-inden-1-one 479.5 133

5,6-dimethoxy-4-(4- methylpiperidin-1-yl)-2-((3 -(trifluoromethyl)pyridin-2- yl)methyl)-2,3-dihydro-1H-inden- 1-one 448.5136

5,6-dimethoxy-4-((1- methylpiperidin-4-yl)amino)-2-(4-((trifluoromethyl)thio)benzyl)-2,3- dihydro-1H-inden-1-one 494.5 138

5,6-dimethoxy-4-((1- methylpiperidin-4-yl)amino)-2-((3-(trifluoromethyl)pyridin-2- yl)methyl)-2,3-dihydro-1H-inden- 1-one 463.5140

6-methoxy-5-(4-methylpiperidin-1- yl)-2-(4-((trifluoromethyl)thio)benzyl)-2,3- dihydro-1H-inden-1-one  450.1* 142

6-methoxy-5-(4-methylpiperidin-1- yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H- inden-1-one 418.4 144

6-methoxy-5-((1-methylpiperidin- 4-yl)amino)-2-(4-((trifluoromethyl)thio)benzyl)-2,3 - dihydro-1H-inden-1-one 464.5 146

6-methoxy-5-((1-methylpiperidin- 4-yl)amino)-2-((3-(trifluoromethyl)pyridin-2- yl)methyl)-2,3-dihydro-1H-inden- 1-one 433.4149

5 -(4-fluoropiperidin-1-yl)-6- methoxy-2-(4-((trifluoromethyl)thio)benzyl)-2,3 - dihydro-1H-inden-1-one 453.5 151

5-(4-fluoropiperidin-1-yl)-6- methoxy-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H-inden- 1-one 422.4 154

6-methoxy-5-(4-methylpiperidin-1- yl)-2-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-1-one 418.* 156

6-methoxy-5-(4-methylpiperazin- 1-yl)-2-(3-(trifluoromethyl)benzyl)-2,3- dihydro-1H-inden-1-one  419.0* 158

2-(2-chloro-5- (trifluoromethyl)benzyl)-6- methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one  440.0* 161

2-(2-chloro-5- (trifluoromethyl)benzyl)-6-methoxy-5-(4-methylpiperazin-1- yl)-2,3-dihydro-1H-inden-1-one 452.9 164

6-methoxy-5-(piperazin-1-yl)-2- ((3-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H-inden- 1-one 405.4 *MS (ESI) m/z (M + H)

TABLE 1B Substituted 2,3-dihydro-1H-inden-1-one containing RORγAntagonists Example ID Structure Name MW 167

4,5-dimethoxy-2-(4- ((trifluoromethyl)thio) benzyl)-2,3-dihydro-1H-inden-1-one 382.40 169

4,5-dimethoxy-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H- inden-1-one 351.32 172

5-chloro-6-methoxy-2-(4- ((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden- 1-one 386.82 174

5-chloro-6-methoxy-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H- inden-1-one 355.74 177

4-chloro-5-methoxy-2-(4- ((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden- 1-one 386.84 179

4-chloro-5-methoxy-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H- inden-1-one 355.06 182

5-methoxy-2-(4- ((trifluoromethyl)thio)benzyl)- 2,3-dihydro-1H-inden-1-one 352.07 184

5-methoxy-2-((3- (trifluoromethyl)pyridin-2- yl)methyl)-2,3-dihydro-1H-inden-1-one 321.10 187

6-hydroxy-5-methoxy-2-(4- ((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden- 1-one 368.01 188

6-methoxy-3-oxo-2-(4- ((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden- 5-yl ethanesulfonate 460.06 190

6-hydroxy-5-methoxy-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H- inden-1-one 337.09 191

6-methoxy-3-oxo-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H- inden-5-yl ethanesulfonate 429.09 193

5-hydroxy-2-(4- ((trifluoromethyl)thio)benzyl)- 2,3-dihydro-1H-inden-1-one 338.06 194

1-oxo-2-(4- ((trifluoromethyl)thio)benzyl)- 2,3-dihydro-1H-inden- 5-ylethanesulfonate 430.05 196

6-hydroxy-5-methoxy-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H- inden-1-one 337.09 197

6-methoxy-3-oxo-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H- inden-5-yl ethanesulfonate 429.09 200

2-(2-fluoro-4- (trifluoromethoxy)phenyl)- 6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1- one 425.13 202

2-(2-fluoro-4- (trifluoromethoxy)phenyl)- 6-methoxy-5-(4-methylpiperazin-1-yl)-2,3- dihydro-1H-inden-1-one 438.16 206

2-(2-fluoro-4- (trifluoromethoxy)phenyl)- 5-(4-fluoropiperidin-1-yl)-6-methoxy-2,3-dihydro- 1H-inden-1-one 441.14 209

2-(2-fluoro-4- (trifluoromethoxy)phenyl)- 5-(4-fluoropiperidin-1-yl)-6-methoxy-2,3-dihydro- 1H-inden-1-one 441.14 213

6-methoxy-5-(2- (trifluoromethoxy)phenyl)- 2-((3-(trifluoromethyl)pyridin-2- yl)methyl)-2,3-dihydro-1H- inden-1-one481.11 216

5-(2-fluoro-4- (trifluoromethoxy)phenyl)- 6-methoxy-2-((3-(trifluoromethyl)pyridin-2- yl)methyl)-2,3-dihydro-1H- inden-1-one499.10 220

2-(2,6-difluoro-3- (1,1,1,3,3,3 -hexafluoro-2- hydroxypropan-2-yl)benzyl)-6-methoxy-5-(4- methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-one 552.17 225

2-(3-(1,1,1,3,3,3- hexafluoro-2- hydroxypropan-2-yl)-5 -(trifluoromethoxy)benzyl)- 6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1- one 587.14 229

2-(3-(1,1,1,3,3,3- hexafluoro-2- hydroxypropan-2-yl)-5-(trifluoromethyl)benzyl)-6- methoxy-5-morpholino-2,3-dihydro-1H-inden-1- one 571.14 232

2-(2,6-difluoro-3- (1,1,1,3,3,3-hexafluoro-2- hydroxypropan-2-yl)benzyl)-6-methoxy-5- morpholino-2,3-dihydro- 1H-inden-1-one 539.13236

2-(3-(1,1,1,3,3,3- hexafluoro-2- hydroxypropan-2-yl)-5 -(trifluoromethoxy)benzyl)- 6-methoxy-5-(4- methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-one 600.17 240

2-(3-(1,1,1,3,3,3- hexafluoro-2- hydroxypropan-2-yl)-5-(trifluoromethyl)benzyl)-6- methoxy-5-(4- methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-one 584.17 242

5-bromo-2-((6-(1,1,1,3,3,3- hexafluoro-2- hydroxypropan-2-yl)pyridin-3-yl)methyl)-6- methoxy-2,3-dihydro-1H- inden-1-one 497.01245

2-((6-(1,1,1,3,3,3- hexafluoro-2- hydroxypropan-2-yl)pyridin-3-yl)methyl)-6- methoxy-5-morpholino- 2,3-dihydro-1H-inden-1-one 504.15 249

6-methoxy-5-(piperazin-1- yl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H- inden-1-one 405.41 250

6-methoxy-5-(4- methylpiperazin-1-yl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H- inden-1-one 419.18 251

5-(4-(2- hydroxyethyl)piperazin-1- yl)-6-methoxy-2-((3-(trifluoromethyl)pyridin-2- yl)methyl)-2,3-dihydro-1H- inden-1-one449.19 256

2-((6-(1,1,1,3,3,3- hexafluoro-2- hydroxypropan-2-yl)pyridin-3-yl)methyl)-6- methoxy-5-(4- methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-one 517.18 264

2-((5-(1,1,1,3,3,3- hexafluoro-2- hydroxypropan-2-yl)pyridin-3-yl)methyl)-6- methoxy-5-morpholino- 2,3-dihydro-1H-inden-1-one 504.42 266

2-((5-(1,1,1,3,3,3- hexafluoro-2- hydroxypropan-2-yl)pyridin-3-yl)methyl)- 6- methoxy-5-morpholino-2,3-dihydro-1H-inden-1- one 504.42 268

2-((5-(1,1,1,3,3,3- hexafluoro-2- hydroxypropan-2-yl)-3-(trifluoromethyl)pyridin-2- yl)methyl)-6-methoxy-5-morpholino-2,3-dihydro- 1H-inden-1-one 572.42 270

2-(2-(1,1,1,3,3,3- hexafluoro-2- hydroxypropan-2-yl)-5-(trifluoromethyl)benzyl)-6- methoxy-5-morpholino-2,3-dihydro-1H-inden-1- one 571.43 *MS (ESI) m/z (M + H)

TABLE 2 List of abbreviation and meaning used through out thisapplication Abbreviation Meaning CHCl3 Chloroform—CHCl₃ CDCl3 Chloroformdeuterated solvent—CDCl₃ DCM Dichloromethane—CH₂Cl₂ DME1,2-Dimethoxyethane DMF N,N-Dimethylformamide DMSO DimethylsulfoxideDMSO-d₆ Dimethylsulfoxide deuterated solvent Pd2(pda)3Tris(dibenzylideneacetone)dipalladium(0) Pd(PH3)4Tetrakis(trifluorophosphine)palladium(0) PTSA p-Tolticrie Sulfanic AcidTHF Tetrahydrofuran ±BINAP rac2.2′-Bis(diphenylphosphino)-9,9-dimethylxanthene Xantphos4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene Pd(dppf)Cl₂·CH₂Cl₂[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium II DCM Et EthylMe Methyl MeOH Methanol EtOH Ethanol EtOAc Ethylacetate AcCN/MeCNAcetonitrile DIPEA Diisopropylethylamine IP Isopropanol Na₂CO₃ SodiumCarbonate K₂CO₃ Potassium Carbonate Cs₂CO₃ Cesium Carbonate TFATrifluoroacetic acid EDC HClN-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide HCl HOBT1-Hydroxybenzotgriazole hydrate HOAc Acetic Acid Et Ethyl TMSTrimethylsilyl NBS N-Bromosuccinamide NCS N-Chlorosuccinamide PGProtecting Group g, gm Gram(s) mg Milligram(s) h, hr Hour min Minute(s)M Molar, molarity mM Millimolar μM Micromolar nM Nanomolar L, 1 Liter(s)mL,mL Milliliter(s) μL Microliter(s) RM Reaction Mixture or ReactionMass SM Starting Material RT, rt Room Temperature HPLC High-PerformanceLiquid Chromatography LCMS Liquid Chromatography Mass Spectrometry MS orms Mass Spectrometry NMR Nuclear Magnetic Resonance Spectroscopy TLCThin Layer Chromatography UV Ultra-Violet Spectrometry s Singlet d, Dt,dt Doublet, doublet of doublet t, tr Triplet m MultipletMethods of Preparation of Compounds

In certain embodiments, the Examples below are compounds preparedaccording to general procedures given in the following sections.Although the synthetic methods and Schemes depict the syntheses ofcertain compounds of the present invention, the methods and othermethods known to one of ordinary skill in the art can be applied to allthe compounds of the genus, the genus sub-class and species of each ofthese compounds as described herein. Aspects of this invention can beunderstood from the following general Schemes 1 and 2. The following areexemplary and are not intended to limit the scope of the invention.

EXAMPLES Experimental Details and Examples

Melting points were determined in a MP-96 digital Polmon apparatus. ¹HNMR and ¹³C NMR spectra were recorded at RT in CDCl₃ or DMSO-d6 at Jeol400-MHz NMR spectrophotometer using solvent peaks for CDCl₃: 7.27 andDMSO-d6 2.50 (D) as internal references. The assignment of chemicalshifts is based on standard NMR experiments (1H, 13C). Mass spectra wererecorded on a Shimadzu LCMS LC-210EVspectrometer with an API-ESionization source. Jasco-FTIR-4100 was used to record the IR spectra.TLC analyses were performed on silica F254 and detection by UV light at254 nm, or by spraying with phosphomolybdic-H₂SO₄ dyeing reagent, KMNO₄or iodine. Column chromatography were performed on silica Gel 60 (230mesh). Purifications and separations were performed on a standard silicaflash chromatography system. The purity of the samples has beendetermined by HPLC for the % area peak corresponding to the retention ofcompound and elemental analysis for C, H, N and O was carried out usingPerkin-Elmer 2400 elemental analyser and chloride analysis performedusing calorimetric titration at the Intertek USA Inc., QTI.

General Synthetic Methodology

The compounds of this invention are prepared in general by methods suchas those depicted in the Schemes below, and the preparative examplesthat follow.

Preparation of Examples Example 16-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one (13)

Step 1:

A solution of 5-bromo-6-methoxy-2,3-dihydro-1H-inden-1-one (11) (1 g,4.149 mmol) and morpholine (0.36 g, 4.149 mmol) in toluene 15 mL wasadded cesium carbonate (2.69 g, 8.298 mmol). The reaction was degassedand purged with nitrogen for 10 min. Pd₂ (dba)₃ (189.3 mg, 0.207 mmol)and BINAP (64.5 mg, 0.103 mmol) was added, degassed and purged and withnitrogen for another 10 min. The reaction was heated to 110° C.overnight under sealed microwave vial. After completion of the startingmaterial, the reaction was diluted with chloroform and filtered throughcelite bed. The organic layer was concentrated to get the crude compound13 and the resulting crude was purified through flash chromatography byusing 100-200 mesh silica gel eluting the compound at 25% ethyl acetatein hexane as pale yellow coloured solid6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 13. ¹HNMR (400 MHz,CDCl₃) δ ppm 7.70 (s, 1H), 7.20 (s, 1H), 3.93 (s, 3H), 3.06 (m, 2H),2.72 (m, 2H); MS (ESI) m/z 247.9 (M+H).

Example 22-(4-chloro-2-fluorobenzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one(16)

Step 2:

To a solution of compound 13 (150 mg, 0.607 mmol) in toluene 15 mL wasadded 14 (86.2 mg, 0.607 mmol). p-Toluene sulphonic acid (PTSA) (230.9mg, 1.214 mmol) was added to the reaction mixture, and stirred at 120°C. for 6 h. The reaction mass was diluted with ethyl acetate and washedwith water (3×25 mL). The organic layer was dried over sodium sulphateand concentrated to get the crude compound 15. The crude compound 15 waspurified through flash chromatography by using 100-200 mesh silica gel.The compound(E)-2-(4-chloro-2-fluorobenzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one15 was eluted at 28% ethyl acetate in hexane to afford a yellow colouredsolid.

Step 3:

Compound 15 (45 mg, 0.121 mmol) was dissolved in methanol and was addedPd/C 20 mg and stirred the reaction under hydrogen balloon for 6 h. Thereaction was filtered through celite bed and washed with excessmethanol. The organic layer was concentrated to get the crude compound16. The crude 16 was purified by flash chromatography using 100-200 meshsilica gel. Compound 16 was eluted at 23% ethyl acetate in hexane ashalf white coloured solid2-(4-chloro-2-fluorobenzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one16. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.18 (m, 2H), 6.82 (m, 3H), 3.88 (m,3H), 3.86 (m, 4H), 3.31 (m, 1H), 3.16 (m, 4H), 3.06 (m, 1H), 2.95 (m,1H), 2.73 (m, 2H); MS (ESI) m/z 389.8 (M+H).

Example 32-(4-chloro-2-fluorobenzyl)-5-(3,4-dimethylpiperazin-1-yl)-6-methoxy-2,3-dihydro-1H-inden-1-one(20)

Example 42-((1-benzylpiperidin-4-yl)methyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one(23)

Step 1:

To a solution of 13 (150 mg, 0.607 mmol) in toluene 15 mL was added1-benzylpiperidine-4-carbaldehyde 21 (123.4 mg, 0.607 mmol). p-Toluenesulphonic acid (PTSA) (230.9 mg, 1.214 mmol) was added to the reactionmixture, and stirred at 120° C. for 6 h. The reaction mass was dilutedwith ethyl acetate and washed with water (3×25 mL). The organic layerwas dried over sodium sulphate and concentrated to get the crudematerial, which was purified through flash chromatography using 100-200mesh silica gel. Eluting at 30% ethyl acetate in hexane gave yellowcoloured solid(E)-2-((1-benzylpiperidin-4-yl)methylene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one22.

Step 2:

Compound 22 (85 mg, 0.195 mmol) was dissolved in methanol 25 mL, addedPd/C 40 mg and stirred under hydrogen balloon for 6 h. The reaction wasfiltered through celite bed and washed with excess methanol. The organiclayer was concentrated to get the crude compound 23. The crude materialwas purified by flash chromatography using 100-200 mesh silica gel. Thecompound was eluted with 20% ethyl acetate in hexane to give half whitecoloured solid compound2-((1-benzylpiperidin-4-yl)methyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one23. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.31 (m, 5H), 7.15 (bs, 1H), 6.85 (bs,1H), 3.88 (m, 7H), 3.51 (bs, 2H), 3.22 (m, 4H), 2.90 (m, 2H), 2.65 (m,2H), 1.90 (m, 3H), 1.64 (m, 2H), 1.58 (bs, 4H); MS (ESI) m/z 435.2(M+H).

Example 52-((1-benzylpiperidin-4-yl)methyl)-5-(3,4-dimethylpiperazin-1-yl)-6-methoxy-2,3-dihydro-1H-inden-1-one(25)

Example 62-(2,4-difluorobenzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one(28)

Step 1:

To a solution of compound 13 (150 mg, 0.607 mmol) in toluene 15 mL wasadded 26 (86.2 mg, 0.607 mmol), then PTSA (230.9 mg, 1.214 mmol) wasadded and stirred at 120° C. for 6 h. The resulting mixture was dilutedwith ethyl acetate and washed with water (3×25 mL). The organic layerwas dried over sodium sulphate and concentrated to get the crudecompound 27, which was purified through flash chromatography using100-200 mesh silica gel. Eluting at 28% ethyl acetate in hexane gaveyellow coloured solid compound(E)-2-(2,4-difluorobenzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one27.

Step 2:

To 27 (45 mg, 0.121 mmol), dissolved in methanol, was added Pd/C 20 mgand stirred under hydrogen balloon for 6 h. The reaction was filteredthrough celite bed and washed with excess methanol. The organic layerwas concentrated to get the crude, which was purified by flashchromatography using 100-200 mesh silica gel. The compound was eluted at23% ethyl acetate in hexane as half white coloured solid compound2-(2,4-difluorobenzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one28. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.18 (m, 2H), 6.82 (m, 3H), 3.88 (m,3H), 3.86 (m, 4H), 3.31 (m, 1H), 3.16 (m, 4H), 3.06 (m, 1H), 2.95 (m,1H), 2.73 (m, 2H); MS (ESI) m/z 373.9 (M+H).

Example 76-methoxy-5-morpholino-2-(3-(trifluoromethoxy)benzyl)-2,3-dihydro-1H-inden-1-one(31)

To a solution of compound 13 (150 mg, 0.607 mmol) in toluene 15 mL wasadded 3-bromo-5-(trifluoromethoxy)benzaldehyde 29 (115.4 mg, 0.607mmol). PTSA (230.9 mg, 1.214 mmol) was added to the reaction mixture,then stirred at 120° C. for 6 h. The reaction mixture was diluted withethyl acetate and washed with water (3×25 mL). The organic layer wasdried over sodium sulphate and concentrated to get the crude compound(E)-2-(3-bromo-5-(trifluoromethoxy)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one30, which was purified through flash chromatography by using 100-200mesh silica gel. Compound 30 was eluted at 25% ethyl acetate in hexaneto afford a yellow coloured solid. To 30 (45 mg, 0.107 mmol), dissolvedin methanol 20 mL, was added Pd/C 20 mg and stirred under hydrogenballoon for 6 h. The reaction was filtered through celite bed and washedwith excess methanol. The organic layer was concentrated to get thecrude des-brominated compound 31. The crude 31 was purified by flashchromatography using 100-200 mesh silica gel. Compound 31 was eluted asdes-brominated compound at 25% ethyl acetate in hexane as half whitecoloured solid compound6-methoxy-5-morpholino-2-(3-(trifluoromethoxy)benzyl)-2,3-dihydro-1H-inden-1-one31. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.43 (m, 4H), 7.18 (s, 1H), 6.81 (s,1H), 3.89 (m, 3H), 3.87 (m, 4H), 3.43 (m, 1H), 3.17 (m, 4H), 3.06 (m,1H), 2.97 (m, 1H), 2.69 (m, 2H); MS (ESI) m/z 422.1 (M+H).

Example 86-methoxy-5-morpholino-2-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-1-one(37)

To a solution of 13 (450 mg, 1.819 mmol) in toluene 10 mL was added3-bromo-5-(trifluoromethyl)benzaldehyde 35 (316.8 mg, 1.819 mmol). PTSA(692.2 mg, 3.639 mmol) was added to the reaction mixture, then stirredat 120° C. for 6 h. The reaction mass was diluted with ethyl acetate andwashed with water (3×25 mL). The organic layer was dried over sodiumsulphate and concentrated to get the crude 36, which was purifiedthrough flash chromatography by using 100-200 mesh silica gel. Thecompound(E)-2-(3-bromo-5-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1Hinden-1-one36 was eluted at 30% ethyl acetate in hexane to afford yellow colouredsolid.

The 36 (570 mg, 1.413 mmol) was dissolved in methanol and was added Pd/C(350 mg), and stirred under hydrogen balloon for 6 h. The reaction wasfiltered through celite bed and washed with excess methanol. The organiclayer was concentrated to get the crude 37, which was purified by flashchromatography using 100-200 mesh silica gel. The compound6-methoxy-5-morpholino-2-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-1-one37 was eluted as des-brominated compound at 28% ethyl acetate in hexaneas half white coloured solid. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.47 (m, 4H),7.18 (s, 1H), 6.81 (s, 1H), 3.89 (m, 3H), 3.87 (m, 3H), 3.40 (m, 1H),3.17 (m, 4H), 3.06 (m, 1H), 2.97 (m, 1H), 2.69 (m, 2H); MS (ESI) m/z406.0 (M+H).

Example 92-(2,6-difluorobenzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one(42)

To a solution of 13 (150 mg, 0.607 mmol) in toluene 15 mL was added3-bromo-2,6-difluorobenzaldehyde 40 (81.4 mg, 0.607 mmol) andsubsequently PTSA (230.9 mg, 1.214 mmol) was added, and stirred at 120°C. for 6 h. The reaction mass was diluted with ethyl acetate and washedwith water (3×25 mL). The organic layer was dried over sodium sulphateand concentrated to get the crude compound 41. The crude 41 was purifiedthrough flash chromatography by using 100-200 mesh silica gel. Thecompound(E)-2-(3-bromo-2,6-difluorobenzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one41 was eluted at 32% ethyl acetate in hexane to afford yellow colouredsolid.

The 41 (40 mg, 0.088 mmol) was dissolved in methanol 15 mL and addedPd/C 20 mg and stirred under hydrogen balloon for 6 h. The reaction wasfiltered through elite bed and washed with excess methanol. The organiclayer was concentrated to get the crude compound 42, which was purifiedby flash chromatography using 100-200 mesh silica gel. The compound2-(2,6-difluorobenzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one42 was eluted as des-brominated compound at 26% ethyl acetate in hexaneas half white coloured solid. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.17 (m, 2H),6.89 (m, 3H), 3.89 (m, 7H), 3.35 (m, 1H), 3.19 (m, 4H), 3.06 (m, 2H),2.76 (m, 2H); MS (ESI) m/z 374.0 (M+H).

Example 102-((4-chloro-2-morpholinothiazol-5-yl)methyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one(47)

Example 112-(3-chloro-5-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one(50)

To a solution of 13 (100 mg, 0.404 mmol) in toluene 5 mL was added3-chloro-5-(trifluoromethyl)benzaldehyde 48 (84.4 mg, 0.404 mmol). PTSA(153.9 mg, 0.809 mmol) was added to the reaction mass, then stirred at120° C. for 6 h. The reaction mass was diluted with ethyl acetate andwashed with water (3×25 mL). The organic layer was dried over sodiumsulphate and concentrated to get the crude compound 49, which waspurified through flash chromatography by using 100-200 mesh silica gel.The compound(E)-2-(3-chloro-5-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one49 was eluted at 35% ethyl acetate in hexane to afford yellow colouredsolid.

The 49 (30 mg, 0.068 mmol) was dissolved in methanol 20 mL, Pd/C 10 mgadded and stirred under hydrogen balloon for 6 h. The reaction wasfiltered through celite bed and washed with excess methanol. The organiclayer was concentrated to get the crude compound 50. The crude 50 waspurified by flash chromatography using 100-200 mesh silica gel. Thecompound2-(3-chloro-5-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one50 was eluted at 28% ethyl acetate in hexane as half white colouredsolid. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.43 (m, 3H), 7.18 (s, 1H), 6.82 (s,1H), 3.90 (m, 3H), 3.87 (m, 4H), 3.37 (m, 1H), 3.17 (m, 4H), 3.09 (m,1H), 2.96 (m, 1H), 2.70 (m, 2H); MS (ESI) m/z 440.0 (M+H).

Example 122-(5-chloro-2-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one(53)

To a solution of 13 (100 mg, 0404 mmol) in toluene 5 mL was added5-chloro-2-(trifluoromethyl)benzaldehyde 51 (84.4 mg, 0.404 mmol) andPTSA (153.9 mg, 0.809 mmol). The reaction was stirred at 120° C. for 6h. The reaction mixture was diluted with ethyl acetate and washed withwater (3×25 mL). The organic layer was dried over sodium sulphate andconcentrated to get the crude compound 52. The crude 52 was purifiedthrough flash chromatography by using 100-200 mesh silica gel. Thecompound(E)-2-(5-chloro-2-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one52 was eluted at 28% ethyl acetate in hexane to afford yellow colouredsolid.

Compound 52 (50 mg, 0.114 mmol) was dissolved in methanol 30 mL, Pd/C 17mg added and the reaction stirred under hydrogen balloon for 6 h. Thereaction was filtered through celite bed and washed with excessmethanol. The organic layer was concentrated to get the crude, which waspurified by flash chromatography using 100-200 mesh silica gel. Thecompound 53 was eluted at 24% ethyl acetate in hexane as half whitecoloured solid compound2-(5-chloro-2-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one53. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.43 (m, 3H), 7.18 (s, 1H), 6.82 (s,1H), 3.90 (m, 3H), 3.87 (m, 4H), 3.48 (d, 1H), 3.38 (m, 1H), 3.17 (m,4H), 3.09 (m, 1H), 2.95 (m, 1H), 2.67 (m, 2H); MS (ESI) m/z 440.0 (M+H).

Example 132-(4-chloro-2-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one(56)

To a solution of 13 (100 mg, 0404 mmol) in toluene 5 mL was addedcompound 4-chloro-2-(trifluoromethyl)benzaldehyde 54 (84.4 mg, 0.404mmol). PTSA (153.9 mg, 0.809 mmol) was added to the reaction mass andstirred at 120° C. for 6 h. The reaction mass was diluted with ethylacetate and washed with water (3×25 mL). The organic layer was driedover sodium sulphate and concentrated to get the crude compound 55,which was purified through flash chromatography by using 100-200 meshsilica gel. The compound 55 was eluted at 28% ethyl acetate in hexane toafford a yellow coloured solid.

Compound 55 (40 mg, 0.104 mmol) was dissolved in methanol 30 mL, Pd/C 14mg added and the reaction stirred under hydrogen balloon for 6 h. Thereaction was filtered through celite bed and washed with excessmethanol. The organic layer was concentrated to get the crude 56. Whichwas purified by flash chromatography using 100-200 mesh silica gel. Thecompound was eluted at 24% ethyl acetate in hexane as half whitecoloured solid2-(4-chloro-2-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one56. ¹HNMR (400 MHz, CDCl₃) δ pp 7.64 (m, 1H), 7.44 (m, 2H), 7.19 (m,2H), 6.81 (s, 1H), 4.00 (bs, 2H), 3.48 (d, 1H), 3.89 (m, 7H), 3.48 (m,4H), 3.17 (m, 5H), 2.90 (m, 1H), 2.64 (m, 1H).

Example 14 2-(2-chloro-6-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one (59)

Example 15 2-((2-chloro-5-(trifluoromethyl) pyridin-3-yl)methyl)-6-methoxy-5-morpholino-2, 3-dihydro-1H-inden-1-one (62)

Example 16 N-(2-((6-methoxy-5-morpholino-1-oxo-2,3-dihydro-1H-inden-2-yl) methyl)-4-(trifluoromethyl) phenyl) pivalamide(65)

Example 17 6methoxy-5-morpholino-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H-inden-1-one(68)

To a solution of 13 (250 mg, 1.010 mmol) in toluene 10 mL was added3-(trifluoromethyl) picolinaldehyde (177.0 mg, 1.010 mmol). PTSA (384.5mg, 2.021 mmol) was added to the reaction mixture and stirred at 120° C.for 6 h. The reaction mass was diluted with ethyl acetate and washedwith water (3×25 mL). The organic layer was dried over sodium sulphateand concentrated to get the crude compound(E)-6-methoxy-5-morpholino-2-((3-(trifluoromethyl)pyridin-2-yl)methylene)-2,3-dihydro-1H-inden-1-one67. The compound 67 was purified through flash chromatography by using100-200 mesh silica gel. The compound was eluted at 34% ethyl acetate inhexane to afford yellow coloured solid.

Compound 67 (80 mg, 0.197 mmol) was dissolved in methanol 15 mL, Pd/C 50mg added, and the reaction stirred under hydrogen balloon for 6 h. Thereaction was filtered through celite bed and washed with excessmethanol. The organic layer was concentrated to get the crude. The crudewas purified by flash chromatography using 100-200 mesh silica gel. Thecompound was eluted at 26% ethyl acetate in hexane as half whitecoloured solid compound 68. ¹HNMR (400 MHz, CDCl₃) δ ppm 8.64 (d, 1H),7.91 (d, 1H), 7.22 (d, 2H), 6.83 (s, 1H), 3.89 (m, 7H), 3.65 (dd, 1H),3.44 (m, 1H), 3.16 (m, 6H), 2.72 (dd, 1H); MS (ESI) m/z 407.0 (M+H).

Example 18 6-methoxy-5-morpholino-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-2,3-dihydro-1H-inden-1-one (71)

To a solution of 13 (100 mg, 0.404 mmol) in toluene 5 ml was added6-(trifluoromethyl) nicotinaldehyde 69 (70.8 mg, 0.404 mmol). PTSA (154mg, 0.808 mmol) was added, and the reaction mixture stirred at 120° C.for 6 h. The reaction mass was diluted with ethyl acetate and washedwith water (3×25 mL). The organic layer was dried over sodium sulphateand concentrated to get the crude compound(E)-6-methoxy-5-morpholino-2-((6-(trifluoromethyl)pyridin-3-yl)methylene)-2,3-dihydro-1H-inden-1-one70. The crude 70 was purified through flash chromatography by using100-200 mesh silica gel. The compound was eluted at 32% ethyl acetate inhexane to afford yellow coloured solid 70.

Compound 70 (55 mg, 0.136 mmol) was dissolved in methanol 20 mL, Pd/C 35mg added, and the reaction stirred under hydrogen balloon for 6 h. Thereaction was filtered through celite bed and washed with excessmethanol. The organic layer was concentrated to get the crude compound71. The crude 71 was purified by flash chromatography using 100-200 meshsilica gel. The compound was eluted at 28% ethyl acetate in hexane ashalf white coloured solid compound6-methoxy-5-morpholino-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-2,3-dihydro-1H-inden-1-one71. ¹HNMR (400 MHz, CDCl₃) δ ppm 8.61 (s, 1H), 7.74 (d, 1H), 7.59 (d,1H), 7.17 (s, 1H), 6.80 (s, 1H), 3.89 (m, 3H), 3.86 (m, 4H), 3.39 (dd,1H), 3.17 (m, 4H), 3.11 (m, 1H), 2.98 (m, 1H), 2.83 (m, 1H), 2.71 (m,1H); MS (ESI) m/z 407.0 (M+H).

Example 196-methoxy-5-morpholino-2-(4-((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-1-one(74)

To a solution of 13 (1.2 g, 4.858 mmol) in toluene 40 mL was added4-((trifluoromethyl)thio)benzaldehyde 72 (1 g, 4.858 mmol). PTSA (1.84g, 9.716 mmol) was added and the reaction mixture was stirred at 120° C.for 6 h. The reaction mass was diluted with ethyl acetate and washedwith water (3×25 mL). The organic layer was dried over sodium sulphateand concentrated to get the crude compound 73, which was purifiedthrough flash chromatography by using 100-200 mesh silica gel. Thecompound(E)-6-methoxy-5-morpholino-2-(4-((trifluoromethyl)thio)benzylidene)-2,3-dihydro-1H-inden-1-one73 was eluted at 37% ethyl acetate in hexane to afford yellow colouredsolid.

Compound 73 (1.0 g, 2.296 mmol) was dissolved in methanol 250 mL, Pd/C400 mg was added, and the reaction was stirred under hydrogen balloonfor 6 h. The result was filtered through celite bed and washed withexcess methanol. The organic layer was concentrated to get the crudecompound 74, which was purified by flash chromatography using 100-200mesh silica gel. The compound was eluted at 30% ethyl acetate in hexaneas half white coloured solid6-methoxy-5-morpholino-2-(4-((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-1-one74. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.56 (d, 2H), 7.28 (d, 2H), 7.18 (s,1H), 6.81 (s, 1H), 3.89 (m, 3H), 3.87 (m, 4H), 3.37 (dd, 1H), 3.15 (m,4H), 3.06 (m, 1H), 2.96 (m, 1H), 2.66 (m, 2H); MS (ESI) m/z 438.0 (M+H).

Example 202-(2-fluoro-5-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one(77)

To a solution of 13 (100 mg, 0.404 mmol) in toluene 10 mL was added2-fluoro-5-(trifluoromethyl)benzaldehyde 75 (77.7 mg, 0404 mmol). PTSA(153.8 mg, 0809 mmol) was added and the reaction mixture stirred at 120°C. for 6 h. The reaction mass was diluted with ethyl acetate and washedwith water (3×25 mL). The organic layer was dried over sodium sulphateand concentrated to get the crude compound 76 which was purified throughflash chromatography by using 100-200 mesh silica gel. The compound(E)-2-(2-fluoro-5-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one76 was eluted at 34% ethyl acetate in hexane to afford yellow colouredsolid.

Compound 76 (50 mg, 0.118 mmol) was dissolved in methanol 20 mL, Pd/C30.6 mg added, and the reaction stirred under hydrogen balloon for 6 h.The result was filtered through celite bed and washed with excessmethanol. The organic layer was concentrated to get the crude which waspurified by flash chromatography using 100-200 mesh silica gel. Thecompound was eluted at 26% ethyl acetate in hexane as half whitecoloured solid compound2-(2-fluoro-5-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one77. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.51 (dd, 1H), 7.48 (m, 1H), 7.15 (m,2H), 6.82 (s, 1H), 3.89 (m, 3H), 3.87 (m, 4H), 3.40 (m, 1H), 3.17 (m,4H), 3.11 (m, 1H), 3.02 (m, 1H), 2.70 (m, 2H); MS (ESI) m/z 424.0 (M+H).

Example 212-(2-fluoro-5-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one(80)

To a solution of 13 (100 mg, 0.404 mmol) in toluene 10 mL was added2-fluoro-3-(trifluoromethyl)benzaldehyde 78 (77.7 mg, 0.404 mmol). PTSA(153.8 mg, 0.809 mmol) was added to the reaction mixture and stirred at120° C. for 6 h. The reaction mass was diluted with ethyl acetate andwashed with water (3×25 mL). The organic layer was dried over sodiumsulphate and concentrated to get the crude compound 79 which waspurified through flash chromatography by using 100-200 mesh silica gel.The compound(E)-2-(2-fluoro-3-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one79 was eluted at 34% ethyl acetate in hexane to afford yellow coloured.

Compound 79 (40 mg, 0.094 mmol) was dissolved in methanol 15 mL, Pd/C 25mg, added, and the reaction stirred under hydrogen balloon for 6 h. Thereaction was filtered through celite bed and washed with excessmethanol. The organic layer was concentrated to get the crude 80 whichwas purified by flash chromatography using 100-200 mesh silica gel. Thecompound was eluted at 30% ethyl acetate in hexane as half whitecoloured solid compound2-(2-fluoro-3-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one80. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.48 (m, 2H), 7.33 (m, 1H), 7.15 (m,1H), 6.82 (s, 1H), 3.88 (m, 3H), 3.86 (m, 4H), 3.47 (dd, 1H), 3.14 (m,4H), 3.08 (m, 1H), 2.83 (m, 1H), 2.55 (m, 2H); MS (ESI) m/z 424.0 (M+H).

Example 22 6-methoxy-5-morpholino-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-2,3-dihydro-1H-inden-1-one (83)

Example 236-methoxy-5-morpholino-2-(4-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-1-one(86)

To a solution of 13 (100 mg, 04048 mmol) in toluene 10 mL was added4-(trifluoromethyl)benzaldehyde 84 (70.4 mg, 0.404 mmol). PTSA (153.9mg, 0.809 mmol) was added to the reaction mass, then stirred at 120° C.for 6 h. The reaction mass was diluted with ethyl acetate and washedwith water (3×25 mL). The organic layer was dried over sodium sulphateand concentrated to get the crude 85 which was purified through flashchromatography by using 100-200 mesh silica gel. The compound 85 waseluted at 28% ethyl acetate in hexane to afford yellow coloured solidcompound(E)-6-methoxy-5-morpholino-2-(4-(trifluoromethyl)benzylidene)-2,3-dihydro-1H-inden-1-one85.

The 85 (50 mg, 0.123 mmol) was dissolved in methanol 20 mL, Pd/C 20 mgadded, and the reaction stirred under hydrogen balloon for 6 h, thenfiltered through celite bed and washed with excess methanol. The organiclayer was concentrated to get the crude 86 which was purified by flashchromatography using 100-200 mesh silica gel. The compound 86 was elutedat 25% ethyl acetate in hexane as half white coloured solid compound6-methoxy-5-morpholino-2-(4-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-1-one86. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.53 (d, 2H), 7.34 (d, 2H), 7.18 (s,1H), 6.80 (s, 1H), 3.89 (m, 3H), 3.86 (m, 4H), 3.38 (m, 1H), 3.15 (m,4H), 3.08 (m, 1H), 2.96 (m, 1H), 2.68 (m, 2H); MS (ESI) m/z 406.0 (M+H).

Example 242-(4-chloro-3-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one(89)

To a solution of 13 (100 mg, 0.404 mmol) in toluene 10 mL was added4-chloro-3-(trifluoromethyl)benzaldehyde 87 (84.4 mg, 0.404 mmol). PTSA(153.8 mg, 0.808 mmol) was added and the reaction was stirred at 120° C.for 6 h. The reaction mass was diluted with ethyl acetate and washedwith water (3×25 mL). The organic layer was dried over sodium sulphateand concentrated to get the crude 88 which was purified through flashchromatography by using 100-200 mesh silica gel. The compound(E)-2-(4-chloro-3-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one88 was eluted at 31% ethyl acetate in hexane to afford yellow colouredsolid.

The 88 (65 mg, 0.148 mmol) was dissolved in ethyl acetate 50 mL, Pd/C 15mg added, and the reaction stirred under hydrogen balloon for 6 h, thenfiltered through celite bed and washed with excess methanol. The organiclayer was concentrated to get the crude compound 89. The crude waspurified by flash chromatography using 100-200 mesh silica gel. Thecompound 89 was eluted at 25% ethyl acetate in hexane as half whitecoloured solid compound2-(4-chloro-3-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one89. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.55 (d, 1H), 7.41 (d, 1H), 7.34 (dd,1H), 7.17 (s, 1H), 6.81 (s, 1H), 3.87 (m, 7H), 3.33 (dd, 1H), 3.17 (m,4H), 3.06 (m, 1H), 2.93 (m, 1H), 2.66 (m, 2H); MS (ESI) m/z 439.9 (M+H).

Example 252-(3-chloro-4-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one(92)

To a solution of 13 (550 mg, 2.226 mmol) in toluene 25 mL was added3-chloro-4-(trifluoromethyl)benzaldehyde 90 (464.2 mg, 2.226 mmol). PTSA(846.7 mg, 4.452 mmol) was added to the reaction, and stirred at 120° C.for 6 h, then diluted with ethyl acetate and washed with water (3×25mL). The organic layer was dried over sodium sulphate and concentratedto get the crude compound 91 which was purified through flashchromatography by using 100-200 mesh silica gel. The compound was elutedat 30% ethyl acetate in hexane to afford yellow coloured solid compound(E)-2-(3-chloro-4-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one91.

The 91 (220 mg, 0.502 mmol) was dissolved in ethyl acetate 150 mL, Pd/C100 mg added, and the reaction stirred under hydrogen balloon for 6 h,then filtered through celite bed and washed with excess methanol. Theorganic layer was concentrated to get the crude 92 which was purified byflash chromatography using 100-200 mesh silica gel. The compound waseluted at 28% ethyl acetate in hexane as half white coloured solidcompound2-(3-chloro-4-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one92. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.59 (d, 1H), 7.49 (d, 1H), 7.31 (m,1H), 7.19 (s, 1H), 6.83 (s, 1H), 3.89 (m, 3H), 3.87 (m, 4H), 3.53 (m,1H), 3.17 (m, 4H), 3.07 (m, 2H), 2.91 (m, 1H), 2.73 (m, 1H); MS (ESI)m/z 440.0 (M+H).

Example 266-methoxy-2-((3-methyl-1H-pyrazol-5-yl)methyl)-5-morpholino-2,-dihydro-1H-inden-1-one(95)

To a solution of 13 (100 mg, 0.404 mmol) in toluene 10 mL was added3-methyl-1H-pyrazole-5-carbaldehyde 93 (70.8 mg, 0.404 mmol). PTSA(153.8 mg, 0.808 mmol) was added to the reaction mass, then stirred at120° C. for 6 h, diluted with ethyl acetate and washed with water (3×25mL). The organic layer was dried over sodium sulphate and concentratedto get the crude 94 and was purified through flash chromatography byusing 100-200 mesh silica gel eluting at 2% MeOH in DCM to afford yellowcoloured solid compound(E)-6-methoxy-2-((3-methyl-1H-pyrazol-5-yl)methylene)-5-morpholino-2,3-dihydro-1H-inden-1-one94.

The 94 (85 mg, 0.250 mmol) was dissolved in methanol 50 mL, Pd/C 55 mgadded, and the reaction stirred under hydrogen balloon for 6 h, filteredthrough celite bed and washed with excess methanol. The organic layerwas concentrated to get the crude 95 and was purified by flashchromatography using 100-200 mesh silica gel. The compound 95 was elutedat 2% MeOH in DCM as half white coloured solid compound6-methoxy-2-((3-methyl-1H-pyrazol-5-yl)methyl)-5-morpholino-2,3-dihydro-1H-inden-1-one95. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.17 (s, 1H), 6.82 (s, 1H), 5.86 (s,1H), 3.88 (m, 3H), 3.86 (m, 4H), 3.18 (m, 6H), 2.97 (m, 1H), 2.81 (m,1H), 2.77 (m, 1H); MS (ESI) m/z 342.0 (M+H).

Example 296-methoxy-5-(4-methylpiperazin-1-yl)-2-(4-((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-1-one(106)

To a solution of 5-bromo-6-methoxy-2,3-dihydro-1H-inden-1-one 11 (250mg, 1.04 mol) and N-methylpiperazine (125 mg, 1.248 mol) in toluene 15mL was added cesium carbonate (677 mg, 2.08 mol). The reaction wasdegassed and purged with nitrogen for 10 min. Pd₂(dba)₃ (4.7 mg, 0.052mol) and BINAP (6.4 mg, 0.104 mol) was added and again degassed andpurged with nitrogen for another 10 min. The reaction was heated to 110°C. overnight under sealed conditions. The reaction was diluted withchloroform and filtered through celite bed. The organic layer wasconcentrated to get the crude compound AS-3061 and was purified throughflash chromatography by using 100-200 mesh silica gel eluting thecompound at 2% methanol in chloroform as pale yellow coloured solidcompound 6-methoxy-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-oneAS-3061. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.24 (s, 1H), 7.16 (s, 1H), 6.90(s, 1H), 4.06 (m, 1H), 3.92 (s, 3H), 3.89 (s, 1H), 3.70 (s, 3H), 3.50(m, 2H), 3.29 (s, 4H), 3.01 (m, 4H), 2.62 (m, 6H), 2.42 (s, 3H); MS(ESI) m/z 260.9 (M+H).

To a solution of 11 (250 mg, 1.04 mol) in toluene 15 mL was added4-((trifluoromethyl)thio)benzaldehyde 72 (235 mg, 1.144 mol). PTSA (357mg, 2.08 mol) was added to the reaction mass, which was stirred at 120°C. for 6 h, diluted with ethyl acetate and washed with water (3×25 mL).The organic layer was dried over sodium sulphate and concentrated to getthe crude compound 104 which was purified through flash chromatographyby using 100-200 mesh silica gel. The compound 104 was eluted at 10%ethyl acetate in hexane to afford yellow coloured solid(E)-5-bromo-6-methoxy-2-(4-((trifluoromethyl)thio)benzylidene)-2,3-dihydro-1H-inden-1-one104.

The 104 (125 mg, 0.467 mol) was dissolved in methanol 25 mL, Pt/C 10 mgadded and the reaction stirred under hydrogen balloon for 6 h, thenfiltered through celite bed and washed with excess methanol. The organiclayer was concentrated to get the crude compound(E)-6-methoxy-5-(4-methylpiperazin-1-yl)-2-(4-((trifluoromethyl)thio)benzylidene)-2,3-dihydro-1H-inden-1-one105 and was purified by flash chromatography using 100-200 mesh silicagel. The compound was eluted at 12% ethyl acetate in hexane as halfwhite coloured solid compound 105.

To a solution of 105 (75 mg, 0.174 mol) and N-methyl piperazine (20.9mg, 0.209 mol) in toluene 15 mL was added cesium carbonate (113.3 mg,0.348 mol). The reaction was degassed and purged with nitrogen for 10min. Pd₂(dba)₃ (7.96 mg, 0.0087 mol) and BINAP (10.8 mg, 0.0174 mol) wasadded and again degassed and purged with nitrogen for another 10 min.The reaction was heated to 110° C. overnight under sealed conditions.The reaction was diluted with chloroform and filtered through celitebed. The organic layer was concentrated to get the crude compound 106and was purified through flash chromatography by using 100-200 meshsilica gel eluting the compound at 5% methanol in chloroform as browncoloured solid6-methoxy-5-(4-methylpiperazin-1-yl)-2-(4-((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-1-one106. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.57 (d, 2H), 7.28 (bs, 2H), 7.20 (s,1H), 6.90 (s, 1H), 3.91 (s, 3H), 3.70 (bs, 4H), 3.35 (d, 2H), 2.99 (bs,5H), 2.73 (bs, 3H); MS (ESI) m/z 451.0 (M+H).

Example 31 6-methoxy-5-(4-methylpiperazin-1-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H-inden-1-one (113)

Example 326-methoxy-5-(piperazin-1-yl)-2-(4-((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-1-one(117)

To a solution of 5-bromo-6-methoxy-2,3-dihydro-1H-inden-1-one 11 (250mg, 1.04 mol), piperazine (107 mg, 1.248 mol) and/or Boc-piperazine intoluene 15 mL was added cesium carbonate (677 mg, 2.08 mol). Thereaction was degassed and purged with nitrogen for 10 min. Pd₂(dba)₃(4.7 mg, 0.052 mol) and BINAP (6.4 mg, 0.104 mol) was added and againdegassed and purged with nitrogen for another 10 min. The reactionmixture was heated to 110° C. overnight under sealed conditions. Aftercompletion, the reaction was diluted with chloroform and filteredthrough celite bed. The organic layer was concentrated to get the crudecompound and was purified through flash chromatography by using 100-200mesh silica gel eluting the compound AS-3065 at 4% methanol inchloroform as pale yellow coloured solid compound6-methoxy-5-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-one AS-3065. ¹HNMR(400 MHz, CDCl₃) δ ppm 7.17 (s, 1H), 6.90 (s, 1H), 3.89 (s, 3H), 3.21(m, 4H), 3.15 (m, 4H), 3.035 (m, 2H), 2.67 (m, 2H).

Example 416-methoxy-5-(4-methylpiperidin-1-yl)-2-(4-((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-1-one(140)

To a solution of compound 5-bromo-6-methoxy-2,3-dihydro-1H-inden-1-one11 (250 mg, 1.04 mol) and 4-methylpiperidine 129 (120 mg, 1.248 mol) intoluene 15 mL was added cesium carbonate (677 mg, 2.08 mol). Thereaction was degassed and purged with nitrogen for 10 min, Pd₂(dba)₃(4.7 mg, 0.052 mol) and BINAP (6.7 mg, 0.104 mol) was added and againdegassed and purged with nitrogen for another 10 min. The reaction washeated to 110° C. overnight under sealed conditions. After completion,the reaction was diluted with chloroform and filtered through celitebed. The organic layer was concentrated to get the crude compoundAS-3070 which was purified through flash chromatography by using 100-200mesh silica gel eluting the compound at 25% ethyl acetate in hexane aspale yellow coloured solid6-methoxy-5-(4-methylpiperidin-1-yl)-2,3-dihydro-1H-inden-1-one AS-3070.¹HNMR (400 MHz, CDCl₃) δ ppm 7.14 (s, 1H), 6.90 (s, 1H), 3.88 (s, 3H),3.60 (d, 2H), 3.00 (m, 2H), 2.64 (m, 4H), 1.73 (m, 2H), 1.41 (m, 3H),0.99 (m, 3H).

To a solution of 5-bromo-6-methoxy-2,3-dihydro-1H-inden-1-one 11 (250mg, 0.1037 mmol) in benzene was added4-((trifluoromethyl)thio)benzaldehyde 72 (213 mg, 0.103 mmol). PTSA (395mg, 0.207 mmol) was added, the reaction mass was stirred at 120° C. for6 h, then diluted with ethyl acetate and washed with water (3×25 mL).The organic layer was dried over sodium sulphate and concentrated to getthe crude compound 104 and was purified through flash chromatography byusing 100-200 mesh silica gel. The compound 104 was eluted at 30% ethylacetate in hexane to afford yellow coloured solid.

To a solution of 104 (150 mg, 0.348 mmol) and 4-methylpiperidine (69 mg,0.696 mmol) in toluene and tBuOH (8:2, 10 mL) was added cesium carbonate228 mg, 0.696). The reaction was degassed and purged with nitrogen for10 min. Pd₂(dba)₃ (15.9 mg, 0.0174 mmol) and BINAP (32.4 mg, 0.15 m·mol)was added and again degassed and purged with nitrogen for another 10min. The reaction was heated to 110° C. for overnight under sealedcondition. The reaction was diluted with chloroform and filtered throughcelite bed. The organic layer was concentrated to get the crude compound139 which was purified through flash chromatography by using 100-200mesh silica gel eluting the compound at 10% ethyl acetate in hexane aspale yellow coloured solid(E)-6-methoxy-5-(4-methylpiperidin-1-yl)-2-(4-((trifluoromethyl)thio)benzylidene)-2,3-dihydro-1H-inden-1-one139.

The 139 (80 mg, 0.178 mmol) was dissolved in methanol 50 mL andRaney-Nickel (8 mg) added and the reaction stirred under hydrogenballoon for 2 h. The reaction was filtered through celite bed and washedwith excess methanol. The organic layer was concentrated to get thecrude compound 140 and purified by flash chromatography using 100-200mesh silica gel. The compound 140 was eluted at 8% ethyl acetate inhexane as half white coloured solid compound6-methoxy-5-(4-methylpiperidin-1-yl)-2-(4-((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-1-one140. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.27 (m, 3H), 7.11 (m, 4H), 6.81 (s,1H), 3.89 (s, 3H), 3.60 (bs, 2H), 3.37 (dd, 1H), 2.94 (m, 2H), 2.59 (m,4H), 0.94 (m, 3H), 0.86 (m, 4H); MS (ESI) m/z 450.1 (M+H).

Example 42 6-methoxy-5-(4-methylpiperidin-1-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H-inden-1-one (142)

Example 436-methoxy-5-((1-methylpiperidin-4-yl)amino)-2-(4-((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-1-one(144)

To a solution of 11 (250 mg, 1.04 mol) in toluene 15 mL was added4-((trifluoromethyl)thio)benzaldehyde 72 (235 mg, 1.144 mol). PTSA (357mg, 2.08 mol) was added, the reaction mixture stirred at 120° C. for 6h, diluted with ethyl acetate and washed with water (3×25 mL). Theorganic layer was dried over sodium sulphate and concentrated to get thecrude compound 104 and was purified through flash chromatography byusing 100-200 mesh silica gel. The resulting compound(E)-5-bromo-6-methoxy-2-(4-((trifluoromethyl)thio)benzylidene)-2,3-dihydro-1H-inden-1-one104 was eluted at 10% ethyl acetate in hexane to afford yellow colouredsolid.

The 104 (125 mg, 0.467 mol) was dissolved in methanol 25 mL, Pt/C 10 mgadded, the reaction stirred under hydrogen balloon for 6 h, filteredthrough celite bed and washed with excess methanol. The organic layerwas concentrated to get the crude compound 143 and was purified by flashchromatography using 100-200 mesh silica gel. The compound5-bromo-6-methoxy-2-(4-((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-1-one143 was eluted at 12% ethyl acetate in hexane as half white colouredsolid.

To a solution of 143 (75 mg, 0.174 mol) and 1-methylpiperidin-4-amine134 (23.8 mg, 0.0208 mol) in toluene 15 mL was added cesium carbonate(113.3 mg, 0.348 mol). The reaction was degassed and purged withnitrogen for 10 min. Pd₂(dba)₃ (7.96 mg, 0.0087 mol) and BINAP (10.8 mg,0.0174 mol) was added and again degassed and purged with nitrogen foranother 10 min. The reaction was heated to 110° C. overnight undersealed conditions. The reaction was diluted with chloroform and filteredthrough celite bed. The organic layer was concentrated to get the crudecompound 144 and was purified through flash chromatography by using100-200 mesh silica gel eluting the compound at 7.5% methanol inchloroform as brown coloured solid6-methoxy-5-((1-methylpiperidin-4-yl)amino)-2-(4-((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-1-one144. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.55 (bs, 2H), 7.28 (bs, 2H), 7.08 (s,1H), 6.42 (s, 1H), 4.99 (s, 1H), 3.89 (s, 3H), 3.37 (m, 4H), 2.84 (m,6H), 2.66 (m, 3H), 2.09 (m, 4H); MS (ESI) m/z 465.0 (M+H).

Example 476-methoxy-5-(4-methylpiperidin-1-yl)-2-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-1-one(146)

To a solution of 11 (200 mg, 0.829 mmol) in toluene was added3-(trifluoromethyl)benzaldehyde 99 (158.86 mg, 0.9128 mmol). PTSA (285.5mg, 172.20 mmol) was added to the reaction mass, then stirred at 120° C.for 6 h, diluted with ethyl acetate and washed with water (3×25 mL). Theorganic layer was dried over sodium sulphate and concentrated to get thecrude compound 152 which was purified through flash chromatography byusing 100-200 mesh silica gel. The compound(E)-5-bromo-6-methoxy-2-(3-(trifluoromethyl)benzylidene)-2,3-dihydro-1H-inden-1-one152 was eluted at 30% ethyl acetate in hexane to afford yellow colouredsolid.

To a solution of 152 (120 mg, 0.3007 mmol) and 4-methylpiperidine 129(60.2 mg, 0.6015 mmol) in toluene was added cesium carbonate (197.2 mg,0.6015 mmol). The reaction was degassed and purged with nitrogen for 10min. Pd₂(dba)₃ (13.7 mg, 0.0150 mmol) and BINAP (28.1 mg, 0.0451 mmol)was added and again degassed and purged with nitrogen for another 10min. The reaction was heated to 110° C. overnight under sealedconditions. The reaction was diluted with chloroform and filteredthrough celite bed. The organic layer was concentrated to get the crudecompound 153 which was purified through flash chromatography by using100-200 mesh silica gel eluting the compound(E)-6-methoxy-5-(4-methylpiperidin-1-yl)-2-(3-(trifluoromethyl)benzylidene)-2,3-dihydro-1H-inden-1-one153 at 25% ethyl acetate in hexane as pale yellow coloured solid.

The 153 (100 mg, 0.240 mmol) was dissolved in methanol and Raney-Nickel(10 mg, 10% v/v) added and the reaction stirred under hydrogen balloonfor 6 h. The reaction was filtered through celite bed and washed withexcess methanol. The organic layer was concentrated to get the crudecompound 154 which was purified by flash chromatography using 100-200mesh silica gel. The compound 154 was eluted at 20% ethyl acetate inhexane as half white coloured solid compound6-methoxy-5-(4-methylpiperidin-1-yl)-2-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-1-one154. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.40 (m, 4H), 7.15 (s, 1H), 6.82 (s,1H), 3.89 (s, 3H), 3.60 (s, 2H), 3.41 (dd, 1H), 2.94 (m, 2H), 2.62 (m,4H), 0.92 (m, 4H), 0.85 (m, 3H); MS (ESI) m/z 418.0 (M+H).

Example 486-methoxy-5-(4-methylpiperazin-1-yl)-2-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-1-one(156)

A solution of 11 (200 mg, 0.829 mmol) in toluene was added3-(trifluoromethyl)benzaldehyde 99 (158.86 mg, 0.9128 mmol). PTSA (285.5mg, 172.20 mmol) was added to the reaction mass. The reaction wasstirred at 120° C. for 6 h. The reaction mass was diluted with ethylacetate and washed with water (3×25 mL). The organic layer was driedover sodium sulphate and concentrated to get the crude compound 152which was purified through flash chromatography by using 100-200 meshsilica gel. The compound(E)-5-bromo-6-methoxy-2-(3-(trifluoromethyl)benzylidene)-2,3-dihydro-1H-inden-1-one152 was eluted at 30% ethyl acetate in hexane to afford yellow colouredsolid.

To a solution of 152 (120 mg, 0.3009 mmol) and 4-methylpiperazine (60.1mg, 0.6105 mmol) in toluene was added cesium carbonate (197.2 mg, 0.6015mmol). The reaction was degassed and purged with nitrogen for 10 min.Pd₂(dba)₃ (13.7 mg, 0.0150 mmol) and BINAP (28.0 mg, 0.0451 mmol) wasadded and again degassed and purged with nitrogen for another 10 min.The reaction was heated to 110° C. overnight under sealed conditions.The reaction was diluted with chloroform and filtered through celiteBed. The organic layer was concentrated to get the crude compound 155which was purified through flash chromatography by using 100-200 meshsilica gel eluting the compound at 25% ethyl acetate in hexane as paleyellow coloured solid(E)-6-methoxy-5-(4-methylpiperazin-1-yl)-2-(3-(trifluoromethyl)benzylidene)-2,3-dihydro-1Hinden-1-one 155.

The 155 (100 mg, 0.241 mmol) was dissolved in methanol and Raney-Nickel(10 mg, 10% v/v) added and the reaction stirred under hydrogen balloonfor 6 h. The reaction was filtered through celite bed and washed withexcess methanol. The organic layer was concentrated to get the crudeproduct 156 which was purified by flash chromatography using 100-200mesh silica gel. The compound 156 was eluted at 20% ethyl acetate inhexane as half white coloured solid6-methoxy-5-(4-methylpiperazin-1-yl)-2-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-1-one156. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.42 (m, 4H), 7.17 (s, 1H), 6.83 (s,1H), 3.41 (dd, 1H), 3.21 (bs, 4H), 3.03 (m, 1H), 2.95 (m, 1H), 2.68 (m,2H), 2.61 (bs, 4H), 2.35 (s, 3H); MS (ESI) m/z 419.0 (M+H).

Example 492-(2-chloro-5-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one(158)

To a solution of 6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 13(0.120 mg, 0.485 mmol) in toluene (10 mL) was added2-chloro-5-(trifluoromethyl)benzaldehyde 75 (0.101 mg, 0.485 mmol). PTSA(0.184 mg, 0.971 mmol) was added to the reaction mass, reaction stirredat 100° C. for 6 h, diluted with ethyl acetate and washed with water(3×25 mL). The organic layer was dried over sodium sulphate andconcentrated to get the crude compound 157 which was purified throughflash chromatography by using 100-200 mesh silica gel. The compound waseluted at 15% ethyl acetate in hexane to afford yellow coloured solid(E)-2-(2-chloro-5-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one157.

The 157 (100 mg, 0.228 mmol) was dissolved in methanol and Pd/C (40 mg)added, the reaction stirred under hydrogen balloon for 6 h, filteredthrough celite bed and washed with excess methanol. The organic layerwas concentrated to get the crude compound 158 which was purified byflash chromatography using 100-200 mesh silica gel. The compound waseluted at 10% ethyl acetate in hexane as half white coloured solid2-(2-chloro-5-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one158. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.43 (m, 3H), 7.20 (s, 1H), 6.84 (s,1H), 3.89 (m, 7H), 3.54 (dd, 1H), 3.14 (m, 4H), 3.07 (m, 2H), 2.75 (m,2H); MS (ESI) m/z 440.0 (M+H).

Example 50 6-methoxy-5-(piperazin-1-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H-inden-1-one (164)

Example 514,5-dimethoxy-2-(4-((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-1-one(167)

To a solution of 4,5-dimethoxy-2,3-dihydro-1H-inden-1-one (165) (100 mg,0.520 mmol) in toluene 15 mL was added4-((trifluoromethyl)thio)benzaldehyde (72) (118.4 mg, 0.572 mmol) andPTSA (178.9 mg, 1.414 mmol). The reaction was stirred at 120° C. for 6h. The resulting reaction mixture was diluted with ethyl acetate andwashed with water (3×25 mL). The organic layer was dried over sodiumsulphate and concentrated to get the crude, which was purified throughflash chromatography by using 100-200 mesh silica gel. The compound waseluted at 25% ethyl acetate in hexane to afford yellow coloured solid of(E)-4,5-dimethoxy-2-(4-((trifluoromethyl)thio)benzylidene)-2,3-dihydro-1H-inden-1-oneintermediate 166.

The 166 (85 mg, 0.223 mmol) was dissolved in methanol 25 ml. Pd/C 20 mgwas added and the reaction stirred under H₂ balloon for 6 h. Thereaction was filtered through Celite bed and washed with excessmethanol. The organic layer was concentrated to get the crude compound4,5-dimethoxy-2-(4-((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-1-one167, which was purified by flash chromatography using 100-200 meshsilica gel. The resulting compound 167 was eluted at 20% ethyl acetatein hexane as half white coloured solid. ¹H NMR (400 MHz, CDCl₃) δ ppm7.56 (m, 3H, 7.29 (m, 2H), 6.96 (d, 1H), 3.94 (s, 3H), 3.85 (s, 3H),3.37 (m, 1H), 3.17 (m, 1H), 2.95 (m, 1H), 2.71 (m, 2H); MS (ESI) m/z382.9 (M+H).

Example 524,5-dimethoxy-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H-inden-1-one(169)

To a solution of 165 (100 mg, 0.518 mmol) in toluene 15 ml was added 66(99.7 mg, 0569 mmol). PTSA (196.8 mg 1.03 mmol) was added to thereaction mass, which was then stirred at 120° C. for 12 h. The reactionmass was diluted with ethyl acetate and washed with water (3×25 ml.).The organic layer was dried over sodium sulphate and concentrated to getthe crude, which was used in the next step with out furtherpurification.

The 168 (100 mg) was dissolved in methanol 25 ml, and Pd/C 15 mg added,and the reaction stirred under H₂ balloon for 6 h. The reaction wasfiltered through celite bed and washed with excess methanol. The organiclayer was concentrated to get the crude 169 and was purified by flashchromatography using 100-200 mesh silica gel. The compound was eluted at20% ethyl acetate in hexane as half white coloured solid 168. ¹H NMR(400 MHz, CDCl₃) δ ppm 8.64 (d, 1H), 7.91 (d, 1H), 7.56 (d, 1H), 6.97(d, 1H), 7.11 (d, 1H), 3.86 (s, 6H), 3.66 (d, 1H), 3.43 (m, 1H), 3.32(m, 1H), 3.17 (m, 1H), 2.74 (dd, 1H); MS-ES+351.9.

Example 535-chloro-6-methoxy-2-(4-((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-1-one(172)

To a solution of 5-chloro-6-methoxy-2,3-dihydro-1H-inden-1-one 170 (100mg, 0.510 mmol) in toluene 15 mL was added4-((trifluoromethyl)thio)benzaldehyde 72 (98.4 mg, 0.561 mmol). PTSA(175.9 mg, 1.2 mmol) was added to the reaction mass, which was stirredat 120° C. for 6 h. The reaction mass was diluted with ethyl acetate andwashed with water (3×25 mL). The organic layer was dried over sodiumsulphate and concentrated to get the crude(E)-5-chloro-6-methoxy-2-(4-((trifluoromethyl)thio)benzylidene)-2,3-dihydro-1H-inden-1-one(171), which was purified through flash chromatography by using 100-200mesh silica gel. The compound was eluted at 22% ethyl acetate in hexaneto afford yellow coloured solid.

The compound 171 (85 mg, 0.195 mmol) was dissolved in methanol 25 mL andPt/C (40 mg) and the reaction stirred under H₂ balloon for 6 h. Thereaction was filtered through celite bed and washed with excessmethanol. The organic layer was concentrated to get the crude. The crudewas purified by flash chromatography using 100-200 mesh silica gel. Thecompound was eluted at 25% ethylacetate in hexane as half white colouredsolid 172. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.57 (d, 2H), 7.43 (s, 1H),7.27 (d, 2H), 7.25 (s, 1H), 3.94 (s, 3H), 3.37 (dd, 1H), 3.11 (m, 1H),2.99 (m, 1H), 2.72 (m, 2H); MS-ES+386.8.

Example 545-chloro-6-methoxy-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H-inden-1-one(174)

To a solution of 170 (150 mg, 0.7769 mmol) in toluene 15 ml was added 66(203.9 mg, 1.165 mmol). PTSA (443.06 mg, 0.2337 mmol) was added to thereaction mass, which was stirred at 120° C. for 6 h. The reaction masswas diluted with ethyl acetate and washed with water (3×25 ml). Theorganic layer was dried over sodium sulphate and concentrated to get thecrude, used for the next step without further purification.

The 173 (50 mg) was dissolved in methanol 25 ml. Pt/C 10 mg was addedand the reaction stirred under H₂ balloon for 6 h. The reaction wasfiltered through celite bed and washed with excess methanol. The organiclayer was concentrated to get the crude. The crude was purified by flashchromatography using 100-200 mesh silica gel. The compound 174 waseluted at 20% ethyl acetate in hexane as half white coloured solid 174.¹H NMR (400 MHz, CDCl₃) δ ppm 8.57 (d, 1H), 7.91 (d, 1H), 7.43 (s, 1H),7.29 (s, 1H), 7.23 (d, 1H), 3.95 (s, 3H), 3.64 (dd, 1H), 3.40 (m, 1H),3.23 (m, 2H), 2.75 (dd, 1H); MS-ES+357.8.

Example 554-chloro-5-methoxy-2-(4-((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-1-one(177)

To a solution of 4-chloro-5-methoxy-2,3-dihydro-1H-inden-1-one 175 (100mg, 0.510 mmol) in toluene 15 mL was added compound 72 (123.4 mg, 0.607mmol). PTSA (230.9 mg, 1.214 mmol) was added to the reaction mass, andstirred at 120° C. for 6 h. The reaction mass was diluted with ethylacetate and washed with water (3×25 mL). The organic layer was driedover sodium sulphate and concentrated to get the crude 176, which waspurified through flash chromatography by using 100-200 mesh silica gel.The compound was eluted at 24% ethyl acetate in hexane to afford yellowcoloured solid.

The(E)-4-chloro-5-methoxy-2-(4-((trifluoromethyl)thio)benzylidene)-2,3-dihydro-1H-inden-1-one176 (75 mg, 0.195 mmol) was dissolved in methanol 25 ml to which wasadded Pt/c 40 mg and the reaction stirred under H₂ balloon for 6 h. Thereaction was filtered through celite bed and washed with excessmethanol. The organic layer was concentrated to get the crude, which waspurified by flash chromatography using 100-200 mesh silica gel. Thefinal compound 177 was eluted at 20% ethylacetate in hexane as halfwhite coloured solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.69 (d, 1H), 7.58(d, 2H), 7.29 (d, 2H), 6.98 (d, 1H), 3.99 (s, 3H), 3.38 (dd, 1H), 3.18(dd, 1H), 2.99 (m, 1H), 2.73 (m, 1H); MS-ES+386.8.

Example 564-chloro-5-methoxy-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H-inden-1-one(179)

To a solution of 175 (100 mg, 0.776 mmol) in toluene 15 ml was added 66(203.9 mg, 1.16 mmol). PTSA (452 mg, 2.303 mmol) was added to thereaction mass and stirred at 120° C. for 6 h. The reaction mass wasdiluted with ethyl acetate and washed with water (3×25 ml). The organiclayer was dried over sodium sulphate and concentrated to get the crude178, used in the next step without further purification

The 178 (70 mg) was dissolved in methanol 25 ml, Pt/C 10 mg added, andthe reaction stirred under H₂ balloon for 6 h. The reaction was filteredthrough celite bed and washed with excess methanol. The organic layerwas concentrated to get the crude, which was purified by flashchromatography using 100-200 mesh silica gel. The compound 179 waseluted at 20% ethyl acetate in hexane as half white coloured solid 179.¹H NMR (400 MHz, CDCl₃) δ ppm 8.60 (d, 1H), 7.91 (d, 1H), 7.72 (d, 1H),7.24 (d, 1H), 6.99 (d, 1H), 4.00 (s, 3H), 3.66 (dd, 1H), 3.44 (m, 1H),3.24 (m, 2H), 2.75 (dd, 1H); MS-ES+355.8.

Example 575-methoxy-2-(4-((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-1-one(182)

To a solution of 180 (100 mg, 0.617 mmol) in toluene 15 mL was added 72(139.4 mg, 0.6787 mmol). PTSA (212.9 mg, 1.234 mmol) was added to thereaction mass, and stirred at 120° C. for 6 h. The reaction mass wasdiluted with ethyl acetate and washed with water (3×25 mL). The organiclayer was dried over sodium sulphate and concentrated to get the crude,which was purified through flash chromatography by using 100-200 meshsilica gel. The compound was eluted at 15% ethyl acetate in hexane toafford 181 as a yellow solid.

The 181 (90 mg, 0.270 mmol) was dissolved in methanol 25 mL, Pd/C 15 mgadded, and the reaction stirred under H₂ balloon for 6 h. The reactionwas filtered through celite bed and washed with excess methanol. Theorganic layer was concentrated to get the crude, which was purified byflash chromatography using 100-200 mesh silica gel. The compound waseluted at 20% ethyl acetate in hexane as half white coloured solid 182.¹H NMR (400 MHz, CDCl₃) δ ppm 7.70 (d, 1H), 7.56 (d, 2H), 7.28 (d, 2H),6.89 (m, 1H), 6.83 (m, 1H), 3.86 (s, 3H), 3.38 (dd, 1H), 3.13 (dd, 1H),2.96 (m, 1H), 2.70 (m, 2H); MS-ES+352.9.

Example 585-methoxy-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H-inden-1-one(184)

A solution of 180 (100 mg, 0.617 mmol) in toluene 15 ml was added 66(151.2 mg, 0.864 mmol). PTSA (234.5 mg, 1.234 mmol) was added to thereaction mass. The reaction was stirred at 120° C. for 6 h. The reactionmass was diluted with ethyl acetate and washed with water (3×25 mL). Theorganic layer was dried over sodium sulphate and concentrated to get thecrude 183, used the next step without further purification.

The 183 (100 mg) was dissolved in methanol 25 ml, Pd/C 10 mg added, andthe reaction stirred under H₂ balloon for 6 h. The reaction was filteredthrough celite bed and washed with excess methanol. The organic layerwas concentrated to get the crude, which was purified by flashchromatography using 100-200 mesh silica gel. The compound 184 waseluted at 12% ethyl acetate in hexane as half white coloured solid 184.¹H NMR (400 MHz, CDCl₃) δ ppm 8.64 (d, 1H), 7.91 (d, 1H), 7.72 (d, 1H),6.90 (d, 1H), 6.85 (s, 1H), 3.87 (s, 3H), 3.65 (dd, 1H), 3.42 (m, 1H),3.27 (m, 1H), 3.15 (m, 1H), 2.79 (dd, 1H); MS-ES+321.8.

Example 596-methoxy-3-oxo-2-(4-((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-5-ylethanesulfonate (188)

To a solution of 185 (50 mg, 0.280 mmol) in toluene 15 mL was added 72(34.4 mg, 0.280 mmol). PTSA (94.129 mg, 0.561 mmol) was added to thereaction mass and stirred at 120° C. for 6 h. The reaction mass wasdiluted with ethyl acetate and washed with water (3×25 mL). The organiclayer was dried over sodium sulphate and concentrated to get the crude,which was purified through flash chromatography by using 100-200 meshsilica gel. The compound 186 was eluted at 30% ethyl acetate in hexaneto afford yellow coloured solid.

The 186 (70 mg 0.195 mmol) was dissolved in methanol 25 mL, Pd/C 30 mgadded, and the reaction stirred under H₂ balloon for 6 h. The reactionwas filtered through celite bed and washed with excess methanol. Theorganic layer was concentrated to get the crude 187 which was purifiedby flash chromatography using 100-200 mesh silica gel. The compound 187was eluted at 20% ethyl acetate in hexane as half white coloured solid.¹H NMR (400 MHz, CDCl₃) δ ppm 7.56 (d, 2H), 7.28 (d, 2H), 6.80 (s, 1H),5.67 (s, 1H), 3.96 (s, 3H), 3.36 (dd, 1H), 3.07 (dd, 1H), 2.94 (m, 1H),2.70 (m, 2H); MS-ES+368.9.

The 187 (50 mg, 0.1366 mmol) was dissolved in acetone and K₂CO₃ (37.7mg, 0.2732 mmol) added followed by ethane sulfonyl chloride (50 mg,0.1366 mmol). The reaction was stirred for 12 h at 70° C., then dilutedwith ethyl acetate and washed with water (3×50 ml). The organic layerwas concentrated to get the crude 188 which was purified by flashchromatography using 100-200 mesh silica gel. The compound was eluted at15% ethyl acetate in hexane as half white coloured solid 188. ¹H NMR(400 MHz, CDCl₃) δ ppm 7.65 (s, 1H), 7.57 (d, 2H), 7.27 (d, 2H), 6.94(s, 1H), 3.95 (s, 3H), 3.35 (m, 3H), 3.14 (m, 1H), 2.99 (m, 1H), 2.71(m, 2H), 1.57 (m, 3H); MS-ES+460.8.

Example 606-methoxy-3-oxo-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H-inden-5-ylethanesulfonate (191)

To a solution of 185 (50 mg, 0.2808 mmol) in toluene 15 ml was added 66(68.8 mg, 0.393 mmol). PTSA (106.7 mg, 0.561 mmol) was added to thereaction mass and stirred at 120° C. for 6 h. The reaction mass wasdiluted with ethyl acetate and washed with water (3×25 ml.). The organiclayer was dried over sodium sulphate and concentrated to get the crude189, which was used for next step without further purification.

The 189 (50 mg) was dissolved in methanol 25 ml, Pd/C 10 mg added, andthe reaction stirred under H₂ balloon for 6 h. The reaction was filteredthrough celite bed and washed with excess methanol. The organic layerwas concentrated to get the crude 190, which was purified by flashchromatography using 100-200 mesh silica gel. The compound was eluted at20% ethyl acetate in hexane as half white coloured solid 190. ¹H NMR(400 MHz, CDCl₃) δ ppm 8.64 (d, 1H), 7.91 (d, 1H), 7.29 (s, 1H), 6.82(s, 1H), 3.97 (s, 3H), 3.64 (dd, 1H), 3.43 (m, 1H), 3.13 (m, 2H), 2.74(dd, 1H); MS-ES+337.8.

The 190 (40 mg, 0.108 mmol) was dissolved in acetone, K₂CO₃ (29.9 mg,0.217 mmol) added, followed by ethane sulfonyl chloride (16.6 mg, 0.103mmol). The reaction was stirred for about 12 h at 70° C. The reactionmass was diluted with ethyl acetate and washed with water (3×50 mL). Theorganic layer was concentrated to get the crude 191, which was purifiedby flash chromatography using 100-200 mesh silica gel. The compound waseluted at 14% ethyl acetate in hexane as half white coloured solid 191.¹H NMR (400 MHz, CDCl₃) δ ppm 8.60 (d, 1H), 7.91 (d, 1H), 7.67 (s, 1H),7.27 (s, 1H), 6.96 (s, 1H), 3.95 (s, 3H), 3.65 (dd, 1H), 3.42 (m, 2H),3.20 (m, 2H), 2.82 (dd, 1H), 1.57 (m, 2H), 1.20 (m, 3H); MS-ES+429.8.

Example 611-oxo-2-(4-((trifluoromethyl)thio)benzyl)-2,3-dihydro-1H-inden-5-ylethanesulfonate (194)

To a solution of 191 (250 mg, 1.688 mmol) in toluene 15 mL was added 72(382.5 mg, 1.858 mmol). PTSA (641.7 mg, 3.376 mmol) was added to thereaction mass, then stirred at 120° C. for 6 h, diluted with ethylacetate, and washed with water (3×25 mL). The organic layer was driedover sodium sulphate and concentrated to get the crude, which waspurified through flash chromatography by using 100-200 mesh silica gel.The compound was eluted at 30% ethyl acetate in hexane to afford yellowcoloured solid 192.

The 192 (250 mg, 0.744 mmol) was dissolved in methanol 25 mL, Pd/C 10 mgadded, and the reaction stirred under H₂ balloon for 6 h. The reactionwas filtered through celite bed and washed with excess methanol. Theorganic layer was concentrated to get the crude, which was purified byflash chromatography using 100-200 mesh silica gel. The compound waseluted at 20% ethylacetate in hexane as half white coloured solid 193.¹H NMR (400 MHz, CDCl₃) δ ppm 7.69 (d, 1H), 7.56 (d, 2H), 7.28 (d, 2H),6.79 (d, 2H), 5.46 (s, 1H), 3.38 (dd, 1H), 3.11 (dd, 1H), 2.97 (m, 1H),2.70 (m, 2H); MS-ES+336.9.

The 193 (100 mg, 0.295 mmol) was dissolved in acetone and K₂CO₃ (62 mg,0.442 mmol) added, followed by ethane sulfonyl chloride (42 mg, 0.324mmol). The reaction was stirred for about 12 h at 70° C. The reactionmass was diluted with acetate and washed with water (3×50 mL). Theorganic layer was concentrated to get the crude, which was purified byflash chromatography using 100-200 mesh silica gel. The compound waseluted at 20% ethyl acetate in hexane as half white coloured solid 194.¹HNMR (400 MHz, CDCl₃) δ ppm 7.81 (d, 1H), 7.58 (d, 2H), 7.34 (s, 1H)7.26 (m, 3H), 3.33 (m, 3H), 3.21 (m, 2H), 3.02 (m, 1H), 2.75 (m, 2H),1.56 (m, 4H), 1.28 (m, 3H); MS-ES+429.0.

Example 626-methoxy-3-oxo-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H-inden-5-ylethanesulfonate (197)

To a solution of 185 (100 mg, 0.6754 mmol) in toluene 15 mL was added 66(130.09 mg, 0.742 mmol). PTSA for 6 h. The reaction mass was dilutedwith ethyl acetate and washed with water (3×25 mL). The organic layerwas dried over sodium sulphate and concentrated to get the crude 195,which was used for next step without further purification.

The 195 (100 mg) was dissolved in methanol 25 ml, Pd/C 20 mg added, andthe reaction stirred under H₂ balloon for 6 h. The reaction was filteredthrough celite bed and washed with excess methanol. The organic layerwas concentrated to get the crude 196, which was purified by flashchromatography using 100-200 mesh silica gel. The compound 196 waseluted at 20% ethyl acetate in hexane as half white coloured solid 196.¹HNMR (400 MHz, CDCl₃) δ ppm 10.4 (s, 1H), 8.74 (d, 1H), 8.14 (d, 1H),7.49 (m, 2H), 6.81 (m, 2H), 3.45 (dd, 1H), 3.18 (m, 2H), 3.01 (m, 1H),2.77 (dd, 1H); MS-ES+307.8.

The 196 (40 mg, 0.1299 mmol) was dissolved in acetone, K₂CO₃ (35.7 mg,0.259 mmol) added, followed by ethane sulfonyl chloride (33.1 mg, 0.259mmol). The reaction was stirred for about 12 h at 70° C. The reactionmass was diluted with acetate and washed with water (3×50 ml). theorganic layer was concentrated to get the crude 197, which was purifiedby flash chromatography using 100-200 mesh silica gel. The compound waseluted at 20% ethyl acetate in hexane as half white coloured solid 197.¹HNMR (400 MHz, CDCl₃) δ ppm 8.56 (d, 1H), 7.91 (d, 1H), 7.83 (d, 1H),7.35 (s, 1H), 7.27 (s, 1H), 3.64 (dd, 1H), 3.41 (m, 1H), 3.31 (m, 4H),2.88 (m, 1H), 1.57 (m, 4H), 1.23 (m 3H); MS-ES+399.9.

Example 636-methoxy-5-(2-(trifluoromethoxy)phenyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H-inden-1-one(213)

To a solution of 203 (100 mg, 0.414 mmol) and(2-(trifluoromethoxy)phenyl) boronic acid (85.32 mg, 0.414 mmol) inacetonitrile was added cesium carbonate (271 mg, 0.826 mmol). Thereaction was degassed and purged with N₂ for 10 min. Pd(dppf)Cl₂ (16.88mg, 0.02 mmol) was added to the reaction, then degassed and purged withnitrogen for another 10 min. The reaction was heated to 90° C. undersealed condition overnight. The reaction mixture was allowed to cool tort, and diluted with chloroform. The organic layer was filtered throughcelite plug and concentrated to get the crude, which was purifiedthrough flash chromatography by using 100-200 mesh silica gel. Thecompound 211 was eluted in 5% ethyl acetate in hexane as half whitesolid 211.

To a solution of 211 (150 mg, 0.465 mmol) and 66 (122 mg, 0.698 mmol) intoluene 15 mL was added PTSA (177 mg, 0.9314 mmol). The reaction wasstirred at 120° C. for 6 h, diluted with ethyl acetate and washed withwater (3×25 mL). The organic layer was dried over sodium sulphate andconcentrated to get the crude 212, which was purified through flashchromatography by using 100-200 mesh silica gel. The compound 212 waseluted at 10% ethyl acetate in hexane to afford yellow coloured solid.

The 212 (70 mg, 0.145 mmol) was dissolved in methanol 25 mL and Pd/C 10mg added. The reaction was stirred under H₂ balloon for 6 h, thenfiltered through celite bed and washed with excess methanol. The organiclayer was concentrated to get the crude 213 which was purified by flashchromatography using 100-200 mesh silica gel. The compound 213 waseluted at 12% ethyl acetate in hexane as half white coloured solid.¹HNMR (400 MHz, CDCl₃) δ ppm 8.16 (d, 1H), 7.92 (d, 1H), 7.41 (m, 1H),7.34 (m, 4H), 7.24 (m, 2H), 3.82 (s, 3H), 3.68 (dd, 1H), 3.49 (m, 1H),3.26 (m, 1H), 2.79 (dd, 1H); MS-ES+482.0.

Example 645-(2-fluoro-4-(trifluoromethoxy)phenyl)-6-methoxy-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H-inden-1-one(216)

To a solution of 203 (100 mg, 0.414 mmol) and(2-fluoro-4-(trifluoromethoxy)phenyl)boronic acid (101.8 mg, 0.456 mmol)in acetonitrile was added cesium carbonate (272.1 mg, 0.829 mmol). Thereaction was degassed and purged with nitrogen for 10 min. Pd(dppf)Cl₂(16.9 mg, 0.020 mmol) was added to the reaction, which was then degassedand purged with nitrogen for another 10 min. The reaction was heated to90° C. under sealed condition overnight, then allowed to cool to rt, anddiluted with chloroform. The organic layer was filtered through celiteplug and concentrated to get the crude 214, which was purified throughflash chromatography by using 100-200 mesh silica gel. The compound waseluted in 5% ethyl acetate in hexane as half white solid 214.

To a solution of 214 (110 mg, 0.322 mmol)) in toluene 15 ml was added 66(84.9 mg, 0.483 mmol). PTSA (122.4 mg, 0.644 mmol) was added to thereaction mass, which was stirred at 120° C. for 6 h. The reaction masswas diluted with ethyl acetate and washed with water (3×25 mL). Theorganic layer was dried over sodium sulphate and concentrated to get thecrude 215, which was purified through flash chromatography by using100-200 mesh silica gel. The compound was eluted at 10% ethyl acetate inhexane to afford yellow coloured solid 215.

The 215 (65 mg, 0.130 mmol) was dissolved in methanol 25 mL, Pd/C 10 mgadded, and the reaction stirred under H₂ balloon for 6 h, filteredthrough celite bed and washed with excess methanol. The organic layerwas concentrated to get the crude 216, which was purified by flashchromatography using 100-200 mesh silica gel. The compound 216 waseluted at 12% ethyl acetate in hexane as half white coloured solid.¹HNMR (400 MHz, CDCl₃) δ ppm 8.63 (d, 1H), 7.92 (d, 1H), 7.36 (m, 2H),7.28 (m, 2H), 7.06 (m, 2H), 3.86 (s, 3H), 3.68 (dd, 1H), 3.48 (m, 1H),3.26 (m, 2H), 2.80 (dd, 1H); MS-ES+500.1.

Example 656-methoxy-5-(4-methylpiperazin-1-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H-inden-1-one(250)

To a solution of 203 (1.0 g, 0.0041 mmol) and tert-butylpiperazine-1-carboxylate (960 mg, 0.00518 mmol) in toluene 15 ml wasadded cesium carbonate (2.69 g, 0.0082 mmol). The reaction was degassedand purged with N₂ for 10 min. Pd₂(dba)₃ (112 mg, 0.000123 mmol) andBINAP (153 mg, 0.000246 mmol) was added and again degassed and purgedwith nitrogen for another 10 min. The reaction was heated to 110° C.overnight under sealed condition, then diluted with chloroform andfiltered through celite bed. The organic layer was concentrated to getthe crude 246, which was purified through flash chromatography by using100-200 mesh silica gel eluting the compound at 25% Ethyl acetate inhexane as pale yellow coloured solid 246.

To a solution of 246 (0.42 g, 0.0012 mmol) in MeOH/H₂O was added 66 (233mg, 0.00133 mmol) and sodium hydroxide (96 mg, 0.0024 mmol). Thereaction was stirred at RT for 6 h, diluted with chloroform, and washedwith water (3×25 mL). The organic layer was dried over sodium sulphateand concentrated to get the crude, which was purified through flashchromatography by using 100-200 mesh silica gel. The compound 247 waseluted at 30% ethyl acetate in hexane to afford yellow coloured solid247.

The 247 (400 mg, 0.0009 mmol) was dissolved in methanol 25 mL and Pd/C40 mg added and the reaction stirred under H₂ balloon for 6 h. Thereaction was filtered through celite bed and washed with excessmethanol. The organic layer was concentrated to get the crude 248, whichwas purified by flash chromatography using 100-200 mesh silica gel. Thecompound was eluted at 20% ethyl acetate in hexane as half whitecoloured solid 248.

To a solution 248 (300 mg, 0.0059 mmol) in DCM was added trifluoroaceticacid 3 ml and kept stirring for 4 h at RT. After completion of thereaction, solvent was evaporated, and remainder diluted with water. Theaqueous layer was washed with ethyl acetate and kept aside. The aqueouslayer pH was adjusted to 9-10, then extracted with chloroform twice. Thecombined organic layer was dried over sodium sulphate and concentratedto get the crude 249, which was titurated with hexane at 5° C. to getpale yellow coloured solid 249.

A solution of 249 (0.15 g, 0.00037 mmol) was dissolved in DCM. Triethylamine (56 mg, 0.00055 mmol) was added to the reaction followed by methyliodide (50 mg, 0.00044 mmol) and kept stirring at RT for 4 h. Aftercompletion of the reaction, it was diluted with DCM and washed withwater twice. The organic layer was died over sodium sulphate andconcentrated to get the crude 250, which was purified through flashchromatography using neutral alumina eluting the compound at 2% MeOH inchloroform as thick sticky solid 250. ¹HNMR (400 MHz, CDCl₃) δ ppm 8.65(d, 1H), 7.91 (d, 1H), 7.27 (d, 1H), 7.20 (s, 1H), 6.90 (s, 1H), 3.90(m, 4H), 3.64 (dd, 1H), 3.42 (m, 1H), 3.03 (m, 4H), 2.65 (m, 4H), 2.36(m, 4H); MS-ES+420.0.

Example 665-(4-(2-hydroxyethyl)piperazin-1-yl)-6-methoxy-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H-inden-1-one(251)

To a stirred solution of 249 (150 mg, 0.00037 mmol) in acetonitrile wasadded potassium carbonate (100 mg, 0.00074 mmol) then 2-bromo ethanol(57 mg, 0.00046 mmol). The stirred reaction mixture was heated to 80° C.for 4 h. After completion of the reaction, it was filtered throughcelite bed and washed with chloroform. The organic layer wasconcentrated to get the crude 251, which was purified through flashchromatography using neutral alumina by eluting the compound at 2%methanol in chloroform to yield compound 251. ¹HNMR (400 MHz, CDCl₃) δppm 8.65 (d, 1H), 7.91 (d, 1H), 7.20 (m, 2H), 6.84 (s, 1H), 3.89 (m,5H), 3.66 (m, 4H), 3.43 (m, 1H), 3.12 (m, 4H), 3.03 (m, 1H), 2.72 (m,4H), 2.63 (m, 3H); MS-ES+450.0.

Example 672-((5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one(245)

To a solution of 13 (0.1 g, 0.404 mmol) in MeOH/H₂O (1:1) was addednicotinaldehyde 241 (0.052 g, 0.484 mmol) and NaOH (0.032 g, 0.808mmol). The reaction was stirred at RT for 6 h, diluted with chloroformand washed with water (3×25 mL). The organic layer was dried over sodiumsulphate and concentrated to get the crude, which was purified throughflash chromatography by using 100-200 mesh silica gel. The compound 242was eluted at 30% ethyl acetate in hexane to afford yellow colouredsolid(E)-6-methoxy-5-morpholino-2-(pyridin-3-ylmethylene)-2,3-dihydro-1H-inden-1-one242.

The 242 (0.1 g 0.297 mmol) was dissolved in methanol 25 ml and Pd/C 40mg added. The reaction was stirred under H₂ balloon for 6 h. Thereaction was filtered through celite bed and washed with excessmethanol. The organic layer was concentrated to get the crude which waspurified by flash chromatography using 100-200 mesh silica gel. Thecompound 243 was eluted at 20% ethyl acetate in hexane as half whitecoloured solid6-methoxy-5-morpholino-2-(pyridin-3-ylmethyl)-2,3-dihydro-1H-inden-1-one243. ¹HNMR (400 MHz, CDCl₃) δ ppm 8.47 (m, 2H), 7.56 (d, 1H), 7.22 (m,1H), 7.17 (s, 1H), 6.84 (s, 1H), 3.89 (m, 3H), 3.87 (m, 4H), 3.30 (dd,1H), 3.07 (m, 4H), 2.99 (m, 1H), 2.95 (m, 1H), 2.70 (m, 2H).

To a stirred solution of 243 (0.08 g, 0.236 mmol) in toluene was addedPTSA (0.090 g, 0.472 mmol) and kept stirring at 120° C.Hexafluoroacetone 244 (0.129 g, 0.590 mmol) was added to the reactionand heated to 100° C. for 16 h. Reaction was cooled to RT, diluted withwater, extracted with ethyl acetate twice, the organic layer dried oversodium sulphate and concentrated to get the crude, which was purifiedthrough flash chromatography by using 100-200 mesh silica gel elutingthe compound at 30% ethyl acetate in hexane as thick sticky solid2-((5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one245. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.06 (m, 2H), 6.88 (s, 1H), 6.90 (s,1H), 6.123 (s, 1H), 3.88 (m, 7H), 3.49 (m, 1H), 3.08 (m, 2H), 3.03 (m,6H), 2.29 (m, 2H).

Example 682-((5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-6-methoxy-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-one(256)

To a solution of6-methoxy-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-one 253 (0.1g, 0.384 mmol) in MeOH/H₂O (1:1) was added nicotinaldehyde (0.049 g,0.461 mmol) and NaOH (0.03 g, 0.768 mmol) was added to the reactionmass, which was then stirred at RT for 6 h. The reaction mass wasdiluted with chloroform and washed with water (3×25 mL). The organiclayer was dried over sodium sulphate and concentrated to get the crude,which was purified through flash chromatography by using 100-200 meshsilica gel. The compound was eluted at 30% ethyl acetate in hexane toafford yellow coloured solid(E)-6-methoxy-5-(4-methylpiperazin-1-yl)-2-(pyridin-3-ylmethylene)-2,3-dihydro-1H-inden-1-one254.

The 254 (0.08 g, 0.229 mmol) was dissolved in methanol 25 ml, Pd/C 20 mgadded and the reaction stirred under H₂ balloon for 6 h. The reactionwas filtered through celite bed and washed with excess methanol. Theorganic layer was concentrated to get the crude, which was purified byflash chromatography using 100-200 mesh silica gel. The compound waseluted at 20% ethyl acetate in hexane as half white coloured solid6-methoxy-5-(4-methylpiperazin-1-yl)-2-(pyridin-3-ylmethyl)-2,3-dihydro-1H-inden-1-one255.

To a stirred solution of 255 (0.05 g, 0.142 mmol) in toluene was addedPTSA (0.054 g, 0.284 mmol) and kept stirring at 120° C.Hexafluoroacetone 244 (0.078 g, 0.356 mmol) was added to the reactionand kept at temperature and stirred for 16 h. Reaction was then cooledto RT, diluted with water, and extracted with ethyl acetate twice, Theorganic layer was dried over sodium sulphate and concentrated to get thecrude, which was purified through flash chromatography by using 100-200mesh silica gel and eluting the compound at 30% ethyl acetate in hexaneas thick sticky solid2-((5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-6-methoxy-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-one256.

Example 695-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)nicotinaldehyde (259)

To a stirred solution of 3,5-dibromo pyridine 257 (1.09 g, 4.60 mmol) indry THF cooled to 0° C., was added isopropyl magnesium chloride (2.4 mL,4.8 mmol) drop wise while stirring for 10 min. Hexafluoroacetone(CF₃—CO—CF₃) 244 was added to the resulting reaction and continuedstirring for another 2 h. After completion of the starting materials,the reaction was quenched with saturated ammonium chloride solution. Theorganic layer was separated and aqueous phase was extracted again withdiethyl ether, the combined organic layer was dried over sodium sulphateand concentrated to get the crude2-(5-bromopyridin-3-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol 258. The crudewas purified through silica gel by using 100-200 mesh silica gel byeluting the compound at 20:5 ethyl acetate in hexane as thick oil ofcompound 258.

To a stirred solution of 258 (0.347 g, 1.07 mmol) in dry THF, cooled to0° C., was added isopropyl magnesium chloride (1.2 mL, 2.4 mmol) dropwise and stirred for 10 min followed by the addition of DMF (0.015 ml,1.94 mmol) to the reaction and stirred for additional 2 h. Aftercompletion of the reaction, it was quenched with saturated ammoniumchloride solution. The organic layer was separated and aqueous phase wasextracted again with diethyl ether, the combined organic layer was driedover sodium sulphate and concentrated to get the crude compound5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)nicotinaldehyde 259 useddirectly to proceed for the next step.

Example 706-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)picolinaldehyde (262)

To a stirred solution of 2,6-dibromo pyridine 260 (2.37 g, 10 mmol) indry THF, cooled to 0° C., n-BuLi 1.4 mmol in hexane (7.9 ml, 11 mmol)was added drop wise, and stirred for 10 min. Then hexafluoroacetone(CF₃—CO—CF₃) 244 was added to the reaction mixture and continuedstirring for another 2 h. After completion of the reaction, it wasquenched with saturated ammonium chloride solution. The organic layerwas separated and aqueous phase was extracted again with diethyl ether,the combined organic layer was dried over sodium sulphate andconcentrated to get the crude compound2-(6-bromopyridin-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol 261, which waspurified through 100-200 mesh silica gel by eluting the compound at 15%Ethylacetate in hexane to get the thick oil compound 261.

To a stirred solution of 261 (0.5 g, 1.54 mmol) in dry THF, cooled to 0°C., n-BuLi (0.118 g, 1.85 mmol) was added drop wise and continuedstirring for 10 min. Then DMF (0.224 g, 3.08 mmol) was added to thereaction mixture while stirring for another 2 h. After completion of thereaction, it was quenched with saturated ammonium chloride solution. Theorganic layer was separated and aqueous phase was extracted again withdiethyl ether, the combined organic layer was dried over sodium sulphateand concentrated to get the crude compound6-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)picolinaldehyde 262.

Example 712-((5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one(264)

To a solution of 13 (0.1 g, 0.40 mmol)), MeOH/H₂O (1:1), was added5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)nicotinaldehyde 259(0.132 g, 0.485 mmol) and NaOH (0.032 g, 0.80 mmol). The reaction wasstirred at RT for 6 h. The reaction mass was diluted with chloroform andwashed with water (3×25 ml). The organic layer was dried over sodiumsulphate and concentrated to get the crude 263, which was purifiedthrough flash chromatography by using 100-200 mesh silica gel. Thecompound was eluted at 30% ethyl acetate in hexane to afford yellowcoloured solid(E)-2-((5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl)methylene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one263.

The 263 (50 mg, 0.090 mmol) was dissolved in methanol 25 ml, Pd/C 40 mgadded, and the reaction stirred under H₂ balloon for 6 h. The reactionwas filtered through celite bed and washed with excess methanol. Theorganic layer was concentrated to get the crude, which was purified byflash chromatography using 100-200 mesh silica gel. The crude compound264 was eluted at 20% ethyl acetate in hexane as half white colouredsolid2-((5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one264.

Example 722-((6-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one(266)

To a solution of 13 (0.1 g, 0.40 mmol)) in MeOH/H₂O (1:1) was added6-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)picolinaldehyde 262(0.132 g, 0.485 mmol), NaOH (0.032 g, 0.80 mmol), and the reactionstirred at RT for 6 h. The reaction mass was diluted with chloroform andwashed with water (3×25 ml). The organic layer was dried over sodiumsulphate and concentrated to get the crude, which was purified throughflash chromatography by using 100-200 mesh silica gel. The compound 265was eluted at 30% ethyl acetate in hexane to afford yellow colouredsolid(E)-2-((6-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-2-yl)methylene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one265.

The 265 (50 mg 0.1 mmol) was dissolved in methanol 25 ml, Pd/C 40 mgadded, and the reaction stirred under H₂ balloon for 6 h. The reactionwas filtered through celite bed and washed with excess methanol. Theorganic layer was concentrated to get the crude 266 and was purified byflash chromatography using 100-200 mesh silica gel. The 266 compound waseluted at 20% ethyl acetate in hexane as half white coloured solid2-((6-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one266.

Example 732-((5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)methyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one(268)

To a stirred solution of 267 (0.1 g, 0.245 mmol) in toluene was addedPTSA (0.094 g, 0.490 mmol) and kept stirring at 120° C. for 1 h. Afterthe addition of hexafluoroacetone 244 (0.134 g, 0.614 mmol), thereaction was heated to 100° C. for 16 h. After completion of thereaction, it was cooled to RT, diluted with water, and extracted withethyl acetate twice. The organic layer was dried over sodium sulphateand concentrated to get the crude compound 268, which was purifiedthrough flash chromatography by using 100-200 mesh silica gel elutingthe compound at 30% ethyl acetate in hexane as thick sticky solidcompound2-((5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)methyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one268.

Example 742-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-5-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one(270)

To a stirred solution of2-(2-chloro-5-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one269 (0.1 g, 0.226 mmol) in dry THF, cooled to 0° C., n-BuLi (0.021 g,0.339 mmol) was added drop wise and the solution stirred for 10 min.Then hexafluoroacetone 244 (0.10 g, 0.453 mmol) was added to thereaction and stirred for another 2 h. After completion of the reaction,it was quenched with saturated ammonium chloride solution. The organiclayer was separated and aqueous phase was extracted again with diethylether, the combined organic layer was dried over sodium sulphate andconcentrated to get the crude 270, which was purified through 100-200mesh silica gel by eluting with 15% ethyl acetate in hexane to give 20mg of compound2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-5-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one270.

Additional Examples of Usage Method Example 75 Structural Modelling ofRORγt

The compounds of Formula I provided in TABLE 1A & 1B were designed usinga crystal structures of RORγt. Nuclear hormone receptor superfamilyRORα/γ contains a signature type II zinc finger DNA binding motif and aligand binding hydrophobic pocket. Three subtypes; RORα, -β, and -γ(NR1F1-3 or RORA-C), have been identified with unique tissuedistributions and biological function. In the thymus, RORα and twoisoforms, γ1 and γ2 (RORγt/ROR-γT), have been identified with RORγtdistinct from the RORγ1 isoform in that it lacks the amino terminus ofRORγ1. A sequence of ROR-γt (NP_001001523, 1-497) search with in thercsb.org provided the 6 homologues X-ray crystal structure templates and3BOW is selected for FFDD strategy lead to the discovery of substituted2,3-dihydro-1H-inden-1-one containing RORγ antagonists depicted in FIG.1 and its analogues.

In Vitro Inhibition Assays Example 76 TR-FRET RORγt Binding Assay

RORγ-LBD contains a 6-His and GST tag peptide from SRC1-2 anaminoterminal biotinyl-CPSSHSSLTERHKILHRLLQEGSPS was employed and the6-His-(GST) RORγ-LBD was used which expressed and purified frombaculovirus infected Sf-21 insect cells from Invitrogen and purifiedusing glutathione sepharose. The assay protocol included 50 μL ofTR-FRET buffer 50 mM KCl, 50 mM TRIS, 1 mM Na-EDTA, 0.1 mM DTT, (pH7.0); 10 nM of 6-His(GST)RORgamma-LBD, 1 nM Anti-6-His-Eu, 0.1 μM ofSRC1_2 peptide and Strep-APC 10 nM. The peptide binding due todose-curves of compounds was added the 0.1% DMSO. Fluorescence atwavelength 340 nm was read in each well of 94 well plates using anEnvision fluorescence reader in Time Resolved mode after overnightincubation at 4° C. Dose-response data and IC₅₀ values are provided inthe TABLE 3.

Example 77 Effects of the Test Compounds on the RORγt-Activated IL-17AProm/LUCPorter™ HEK 293 Cells

Antagonistic (or inverse agonistic) effects of the test compounds on theRORγt-activated IL-17A Prom/LUCPorter™ HEK 293 cells were analyzed andIC50 of each compound was evaluated. The IL-17A Prom/LUCPorter™ HEK 293cell line (IMGENEX, IML-301) was plated in 96-well white plates at0.75×105 cells per well for overnight. Cells were transfected with theRORγt plasmid (IMGENEX, IMP-122) for 6 h. Cells were treated with aseries of 8 point concentrations of each compound (100, 33.33, 11.11,3.70, 1.23, 0.41, 0.14 and 0.0457 μM) for 16 h. Luciferase activity wasanalyzed using the luciferase reporter assay reagent (IMGENEX, LS100).The data were analyzed using Excel and Prism software. Percent activitywas defined as 100×(1−(Well−Control A)/(Control B−Control A)), whereControl A was the wells containing cells transfected with RORγt andControl B was the wells containing non-transfected cells. Both ControlsA and B were treated with vehicle alone.

IC₅₀ evaluation of selected compound from the TABLE 1 on RORγt-mediatedIL-17A promoter activity and its 10 dose-response curve is given inFIGS. 2 and 3.

Example 78 Cytokine IL-17 Estimation by HTRF

The assay was designed to assess the potency of test compounds on IL-17cytokine release from CD4+T cells. In order to aid in the identificationof potent inhibitors, the IC₅₀'s determined for the test compounds IL-17release from CD4+T cells through the generation of 10 point DoseResponse Curves (DRC). Assay methods used to quantify IL-17 secretion isHTRF (Homogenous Time Resolved Fluorescence). IL-17 secreted is detectedby anti-IL-17 MAb labeled with XL665, the second MAb labeled withCryptate, which binds to specific epitopes of human IL-17. Upon closeproximity of both acceptor and donor energy transfer (FRET) occurs. Thistechnique has been further enhanced by using long-lived labels combinedwith the detection on a time-resolved fluorescence basis, allowingmaximization of prompt fluorescence interferences.

The assay was performed according to manufacturer's instruction. All thereagents were reconstituted according to instructions provided. Thereagents were dispensed into a half area 96-well plate in the followingorder: 10 μL standard or sample, IL-17 MAbXL665 and 5 μL IL-17 Cryptate.For the negative control, the standard or sample is replaced by 10 μL ofdiluent. The plate is covered with a plate sealer and incubated at rtfor 2 h. Following incubation, the plate sealer is removed and the plateis read using HTRF protocol on Envision Microplate reader. All of thedata analysis was carried out using Microsoft Excel (2010) and IC₅₀ wasdetermined using GraphPad Prism 4 software. % Inhibition of the testcompounds were determined utilizing the following formula:% Inhibition=100−(100*(Average Test Compound Counts−Average NegativeControl Counts)/(Average Positive Control Counts−Average NegativeControl Counts)).Dose-response data and IC₅₀ values are provided in the TABLE 3.

TABLE 3 List of substituted 2, 3-dihydro-1H-inden-1-one containingcompounds and corresponding RORγt antagonistic, cellular and IL-17inhibition results* RORγt RORγt IL-17 Example ID Binding Cell SpecificInhibition 16 ** ** ** 20 ** * ** 23 *** ** *** 25 NA * NA 28 ** * ** 31** * ** 34 NA NA NA 30 * * ** 32 *** *** ** 37 *** *** *** 39 NA NA NA42 ** NA ** 44 NA NA * 47 ** ** ** 50 *** ** ** 53 ** ** ** 56 ** ** **59 ** * ** 62 ** ** *** 65 * ** ** 68 *** *** *** 71 * * ** 74 * * ** 77** ** ** 80 ** ** ** 83 ** ** ** 86 ** ** ** 89 ** ** *** 92 ** ** ** 95** ** ** 98 NA NA NA 103 *** ** ** 106 *** ** ** 110 *** *** ** 113 ****** ** 117 *** ** ** 120 NA NA NA 123 ** ** ** 125 ** ** ** 128 ** ** **131 ** ** ** 133 ** ** ** 136 NA NA NA 138 NA NA NA 140 *** ** * 142 **** *** 144 ** ** ** 146 ** ** *** 149 *** * ** 151 ** ** ** 154 ** ***** 156 * *** ** 158 *** ** *** 161 ** *** ** 164 *** ** *** 167 ** ***** 169 ** ** *** 172 ** ** *** 174 ** ** *** 177 *** ** *** 179 *** ***** 182 ** ** *** 184 *** ** *** 187 ** ** *** 188 *** ** *** 190 *** ***** 191 *** *** *** 193 *** *** *** 194 *** *** *** 196 *** ** ** 197*** *** *** 200 NA NA NA 202 NA NA NA 206 NA NA NA 209 NA NA NA 213 ***** *** 216 ** ** *** 220 NA NA NA 225 NA NA NA 229 *** *** *** 232 ****** *** 236 ** ** *** 240 *** *** *** 242 *** *** *** 245 ** *** ** 249** *** ** 250 ** *** ** 251 *** *** *** 256 *** *** *** 264 *** *** ***266 *** *** *** 268 *** *** *** 270 NA NA NA *RORγt antagonistic,cellular and IL-17 inhibition activity result for selected compounds ***<0.5 μM, ** >1.0 μM, * >10 μM NA = Not Available

In Vivo Models Experiment Example 79

Efficacy of substituted 2,3-dihydro-1H-inden-1-one containing selectedcompounds on Inhibition of Anti-CD3e Antibody induced CD4⁺T cellCytokine-IL-17 Production in Male BALB/c Mice

In Vivo Mice Cytokine IL-17 by ELISA Method:

A quantitative analysis of mouse IL-17 sandwich ELISA was conducted fromthe collected serum samples (Mouse IL-17 ELISA Ready-DuoSet ELISA kit,from R&D Systems, USA). The serum samples tested were collected frommice after 1.5 h of anti-CD3e antibody challenge, before antibodychallenge, the mice were treated with different doses of test compoundsor Dexamethasone as mentioned above in experimental design. The captureantibody was diluted in coating buffer (1×PBS) and transferred into eachwell. The plate was sealed and incubated overnight at RT. The followingday the wells of the plate were aspirated and washed (3 times), allowinga one minute soak time in each step. The plate was blocked using 1% BSAin PBS, sealed, and incubated in ambient conditions for not less thanone hour. After the incubation period, the plate was washed as describedabove, and the standards and serum samples were added to the appropriatewells and incubated for two hours at RT. The samples were diluted in a1:10 ratio with 1% BSA in PBS (reagent diluent). After two hours, wellwere washed as mentioned above three times and added the detectionantibody and incubated for two hours. After washing (as mentionedabove), the HRP enzyme is added and incubated for 20 min and washedagain and added substrate according to the manufacturer's instructionsand incubated for 30 min/until blue color develops. The plate was readat 450/570 nm using the Microplate Absorbance Reader (SpectraMax; M3).Statistics: One-Way ANOVA was performed followed by Dunnett's multiplecomparison test. Percent inhibition of cytokine production wascalculated for all groups compared to positive control.

IL-17 Production:

Intravenous administration of 5 ug/animal anti-CD3e antibody to eachmice resulted in significant elevation of IL-17 production at 1.5 h timepoint compared to negative control group. Oral administration of testcompounds 10 mg/kg, 20 mins prior to antibody administration resulted in50% respectively. Dexamethasone treatment showed 94%, respectively,reduction in IL-17 production when compared to positive control group.Data is shown in FIG. 4.

Example 80 Pharmacokinetic Experiments

The bio-availability and pharmacokinetics of some compounds of thepresent invention were examined in male Sprague Dawley rats. A total of6 male rats were used in the study. The study was performed usingparallel design (n=3) with serial sampling.

Dose formulations were prepared on the day of doing. Blood samples werecollected at 0.083 (only IV), 0.25, 0.5, 1, 2, 4, 8 and 24 h post-dose.At each time point, approximately 0.2 mL of blood was withdrawn fromeach cannulated rat through jugular vein and transferred to apre-labeled microfuge tube containing 20 μL of 200 mm K2EDTA per mL ofblood. Following collection of blood sample, equal volume of heparinizedsaline was flushed into jugular vein of rat. The blood samples werecentrifuged at 5000 g for 5 min at 4±2° C. The plasma was separatedwithin 30 min of scheduled time and stored below −60° C. untilbio-analysis. The plasma samples were analyzed for selected testEXAMPLES using a fixed-for purpose liquid chromatographic tandem massspectrometric detection (LC-MS/MS) method with a lower limit ofquantification of 2.21 ng/mL. The pharmacokinetic parameters for selectEXAMPLES were calculated using the non-compartmental analysis tool ofvalidated WinNonlin® software (Version 5.2).

Pharmacokinetic parameters (mean±SD; n=3) of 7 following intravenousbolus and oral gavage administration of 7 solution in male SpragueDawley rats are shown in TABLE 4 below:

TABLE 4 Rat PK: The pharmacokinetic profiles of substituted 2,3-dihydro-1H-inden-1-one containing compounds following intravenousbolus administration and oral gavage in male Sprague Dawley rats. Formu-Route/Dose T_(max) C_(max) AUC_(last) AUC_(inf) CL V₃₅ T_(1/2) lationGroup (mg/kg) (h) (ng/mL) (ng · h/mL) (ng · h/mL) (mL/min/kg) (L/kg) (h)F^(a) Solution 1 IV/2 n/a 1937.82 ± 571.57 ± 589.36 ± 56.98 ± 7.18 ±6.63 ± 19 481.94 57.37 63.88 5.85 2.00 4.92 2 PO/10 2.00^(c) 176.16 ±552.65 ± 557.70 ± n/a n/a n/a (1.00- 22.73 123.98 124.96 2.00)^(a)AUC_(inf) and nominal doses were used for bioavailability (F)calculation; ^(b)back extrapolated concentration at time zero;^(c)T_(max) reported as median (min-max); n/a: not applicable

Example 81 Assessment of the Potency of Test Compounds on IL-17 Releasefrom CD4+T Cells

We have established robust in vitro cell-based HTRF assay for theactivation and stimulation of CD4+T lymphocytes to T helper 17 (Th17)cell differentiation and IL-17 production. The test compounds areselective small-molecule inhibitors of RORγt, was found to inhibit IL-17production, with an IC₅₀ of 220 nM to 1.2 μM. The assay quantificationwas performed using a standard Dex and SB203589 reported to inhibitIL-17, with an IC₅₀ of 14 & 37 nM respectively. These series ofcompounds dose dependently inhibited CD4⁺T cell pool and exhausted IL-17release from mouse splenocytes.

Example 82 Efficacy of Dihydro-1H-Inden-1-One Class Analogues inMOG₃₅₋₅₅ Induced EAE in Female C57BL/6 Mice

To establish the in vivo proof-of-concept in chronic mouse MOG EAEmodel, the lead dihydro-1H-inden-1-one class analogues was administeredorally for QD 28 days as a prophylactic treatment where the diseaseseverity was successfully controlled for dihydro-1H-inden-1-one classanalogues and control Fingolimod (FIG. 5). The cumulative EAE scores(Scale: 0-3.5) of 0.2, 0.0, 0.4, 0.7, 0.1 on days 9-18 (p=0.001) andreached to 0 on day 18 to until day 28^(th) (p=0.001) fordihydro-1H-inden-1-one class analogues and similar scores observed forFingolimod as well (FIG. 6). The results are striking for this study,whereas the positive control (disease mice) with an EAE score of >3.0(>95% disease incidence). The dihydro-1H-inden-1-one class treated micewas well tolerated through put the study with optimal body conditionsand had no signs of Clinical Chemistry changes or toxicity eventsobserved throughout the study. All the mice in the treatment groups aresimilar body weights to that of vehicle treated group. Oraldihydro-1H-inden-1-one class analogues treatment from this studyprovided a compelling evidence of its RORγt antagonistic activity,translating cellular efficacy in to in vivo further supports theseseries of compounds for MS and other indications claimed. All referencesare incorporated by reference herein in their entireties.

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What is claimed is:
 1. A compound according to Formula I:

or pharmaceutically acceptable salts thereof, wherein: X is O R¹ is

or R¹ is C₁₋₄alkyl optionally substituted with 1-6 independent halosubstituents; or R¹ is phenyl, pyridinyl, or pyrazolyl, each optionallysubstituted with 1-5 independent halo, trifluoromethyl,(trifluoromethyl)thio, trifluoromethoxy,1,1,1,3,3,3,-hexafluoro-2-hydroxypropan-2-yl,

substituents; m is 0 or 1; the dotted line indicates an optional doublebond when m=1; R² is halo, —OH, —CN, —OCH₃, —O—S(O)₂CH₂CH₃,

or phenyl optionally substituted with 0-5 independent halo,trifluoromethoxy substituents; R¹ is

n is 2 or 3 carbon chain; and R⁴ is H, OH, OCH₃, or —O—S(O)₂CH₂CH₃.
 2. Acompound selected from:

or a pharmaceutically acceptable salt thereof. 3.6-methoxy-5-morpholino-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-1H-inden-1-onehaving the formula

or a pharmaceutically acceptable salt thereof.
 4. The compound accordingto claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is


5. The compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein R¹ is


6. The compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein R¹ is C₁₋₄alkyl optionally substituted with 1-6independent halo substituents.
 7. The compound according to claim 1, ora pharmaceutically acceptable salt thereof, wherein R¹ is phenyl,optionally substituted with 1-5 independent halo, trifluoromethyl,(trifluoromethyl)thio, trifluoromethoxy,1,1,1,3,3,3,-hexafluoro-2-hydroxypropan-2-yl,

substituents.
 8. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is pyridinyl,optionally substituted with 1-5 independent halo, trifluoromethyl,(trifluoromethyl)thio, trifluoromethoxy,1,1,1,3,3,3,-hexafluoro-2-hydroxypropan-2-yl,

substituents.
 9. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is pyrazolyloptionally substituted with 1-5 independent halo, trifluoromethyl,(trifluoromethyl)thio, trifluoromethoxy,1,1,1,3,3,3,-hexafluoro-2-hydroxypropan-2-yl,

substituents.